Aroyl-piperazine derivatives, their preparation and their use as tachykinin antagonists

ABSTRACT

This invention relates to piperazine derivatives of formula (I), wherein Y is bond or lower alkylene, R1 is aryl which may have substituent(s), R2 is aryl or indolyl, each of which may have substituent(s), R3 is hydrogen or lower alkyl, and R4 is as defined in the description, and its pharmaceutically acceptable salt, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a use of the same for treating or preventing Tachykinin-mediated diseases in human beings or animals.

TECHNICAL FIELD

[0001] The present invention relates to new piperazine derivatives and asalt thereof.

[0002] More particularly, it relates to new piperazine derivatives and asalt thereof Which have pharmacological activities such as Tachykininantagonism, especially Substance P antagonism, Neurokinin A antagonism,Neurokinin B antagonism, and the like, to a process for preparationthereof, to a pharmaceutical composition comprising the same, and to ause of the same as a medicament.

[0003] Accordingly, one object of the present invention is to providenew and useful piperazine derivatives and a salt thereof which havepharmacological activities such as Tachykinin antagonism, especiallySubstance P antagonism, Neurokinin A antagonism, Neurokinin Bantagonism, and the like.

[0004] Another object of the present invention is to provide a processfor tne Preparation of said piperazine derivatives and a salt thereof.

[0005] A further object of the present Invention is to provide apharmaceutical composition comprising, as an active ingredient, saidpiperazine derivatives and a pharmaceutically acceptable salt thereof.

[0006] Still further object of the present invention is to provide a useof said piperazine derivatives or a pharmaceutically acceptable saltthereof as Tachykinin antagonist, especially Substance P antagonist,Neurokinin A antagonist or Neurokinin B antagonist, useful for treatingor preventing Tachykinin-mediated diseases, for example, respiratorydiseases such as asthma, bronchitis, rhinitis, cough, expectoration, andthe like; ophthalmic diseases such as coinjunctivitis, vernalconjunctivitis, and the like; cutaneous diseases such as contactdermiatitis, atopic dermatitis, urticaria, and other eczematoiddermatitis, and the like; inflammatory diseases such as rheumatoidarthritis, osteoarthritis, and the like; pains or aches (e.g., migraine,headache, toothache, cancerous pain, back pain, etc.); and the like inhuman being or animals.

[0007] Some piperazine derivatives having pharmaceutical activities suchas Tachykinin antagonism have been known as described in EP 0655442 A1and WO 97/22597 A1.

DISCLOSURE OF INVENTION

[0008] The object compound of the present invention can be representedby the following general formula (I):

[0009] wherein

[0010] Y is bond or lower alkylene,

[0011] R¹ is aryl which may have substltuent(s),

[0012] R² is aryl or indolyl, each of which may have substituent(s),

[0013] R³ is hydrogen or lower alkyl,

[0014] R⁴ is pyridyl(lower)alkylamino(lower)alkynyl;

[0015] N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino(lower)-alkyl;

[0016] hydroxy (lower)alkoxy(lower)alkyl;

[0017] lower alkanoyl((lower)alkoxy(lower)alkyl;

[0018] phenyl (lower) alkyl which has hydroxy(lower)alkyl ormorpholinyl(lower)alkyl;

[0019] ar(lower)alkoxycarbonyl:

[0020] (2-pyridyl)(lower)alkyl which may have 1 to 3 substituent(s)selected from the group consisting of lower alkyl, lower alkoxy, loweralkoxycarbonyl, mono(or di or tri)halo(lower)alkyl and halogen;

[0021] (3-pyridyl)propyl which may have lower alkoxy or amino;

[0022] (3-pyridyl)butyl which may have lower alkoxy or amino;

[0023] pyridyl(lower)alkenyl which may have lower alkoxy or amino;

[0024] (2-pyridyl)(lower)alkynyl which may have 1 to 3 substituent(s)selected from the group consisting of lower alkyl, lower alkoxy, loweralkoxycarbonyl, mono(or di or tri)halo(lower)alkyl and halogen;

[0025] (3-pyridyl)(lower)alkynyl which may have lower alkoxy or amino;

[0026] pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which mayhave substituent(s);

[0027] imidazolyl(lower)alkyl which may have 1 or 2 substituent(s)selected from the group consisting of lower alkyl, lower alkynyl,ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyland halogen;

[0028] pyrazolyl(lower)alkyl which may have hydroxy(lower)alkyl,carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl,morpholinyl(lower)alkyl or morpholinylcarbonyl(lower)alkyl;

[0029] thiazolyl(lower)alkyl which may have lower alkyl;

[0030] piperidyl(lower)alkyl which may have hydroxy(lower)alkyl or loweralkoxy;

[0031] morpholinyl(lower)alkyl which has 1 or 2 substituent(s) selectedfrom the group consisting of ethyl, hydroxy(lower)alkyl,halo(lower)alkyl and lower alkoxy(lower) alkyl;

[0032] morpholinyl(lower)alkyl which has lower alkyl and loweralkoxy(lower)alkyl;

[0033] (3,5-dimethylmorpholino)(lower)alkyl;

[0034] morpholino(lower)alkenyl which may have lower alkyl or loweralkoxy(lower)alkyl;

[0035] (2- or 3-morpholinyl)(lower)alkenyl which may have loweralkoxycarbonyl;

[0036] pyrrolidinyl(lower)alkynyl which may have loweralkoxy(lower)alkyl;

[0037] morpholinyl(lower)alkynyl which may have 1 or 2 substituent(s)selected from the group consisting of ethyl, propyl, isopropyl,isobutyl, spirocyclo(lower)-alkyl, lower alkoxy(lower)alkyl,hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl,lower alkoxycarbonyl and halo(lower)alkyl;

[0038] morpholinyl(lower)alkynyl which has methyl and lower alkoxy;

[0039] (dimethylmorpholino)(lower)alkynyl;

[0040] homomorpholinyl(lower)alkynyl which have halogen;

[0041] (morpholinylamino)propyl which may have lower alkanoyl;

[0042] thiomorpholinyl(lower)alkynyl which may have substituent(s);

[0043] homomorpholinylamino(lower)alkyl;

[0044] thiomorpholinylamino(lower)alkyl; or

[0045] saturated heterocyclicimino(lower)alkyl, saturatedheterocyclicaminocarbonyl(lower)alkyl or saturatedheterocyclic(lower)alkoxy(lower)alkyl, each of which may havesubstituent(s),

[0046] provided that when

[0047] R⁴ is 2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl,

[0048] 3-(3-pyridyl)propyl,

[0049] 3-(3-pyridyl)-2-propynyl,

[0050] 4-[(2-methoxymethyl)pyrrolidino]-2-butynyl,

[0051] 4-thiomorpholino-2-butynyl,

[0052] 3-(morphlinoamino)propyl,

[0053] 4-morpholino-2-butenyl, 4-morpholino-2-butynyl, or

[0054] 4-(3,3-dimethylmorpholino)-2-butynyl, then

[0055] R¹ is not 3,5-bis(trifluoromethyl)phenyl.

[0056] It is to be noted that the object compound (I) may include one ormore stereoisomers due to asymmetric carbon atom(s) and double bond, andall of such isomers and a mixture thereof are included within the scopeof the present invention.

[0057] A It is further to be noted that isomerization or rearrangementof the object compound (I) may occur due to the effect of the light,acid, base or the like, and the compound obtained as the result of saidisomerization or rearrangement is also included within the scope of thepresent invention.

[0058] It is also to be noted that the solvating form of the compound(I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I)are included within the scope of the present invention.

[0059] According to the present invention, the object compound (I) or asalt thereof can be prepared by processes which are illustrated in thefollowing schemes.

[0060] wherein

[0061] Y, R¹, R², R³ and R⁴ are each as defined above,

[0062] X₁, X₂ and X₃ are each lower alkylene,

[0063] Z₁ and Z₃ are each lower alkynylene,

[0064] Z₂ is lower alkenylene,

[0065] R⁵ is 2-pyridyl which may have 1 to 3 substituent(s) selectedfrom the group consisting of lower alkyl, lower alkoxy, loweralkoxycarbonyl, mono(or di or tri)halo(lower)alkyl and halogen; or

[0066] 3-pyridyl which may have lower alkoxy or amino,

[0067] R⁶ is saturated heterocyclic which may have substituent(s),

[0068] R⁷ is pyridyl(lower)alkylamino;

[0069] N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino;

[0070] 1-imidazolyl which may have 1 or 2 substituent(s) selected fromthe group consisting of lower alkyl, lower alkynyl, ar(lower)alkyl,pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen;

[0071] 1-pyrazolyl which may have hydroxy(lower)alkyl,carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl,morpholinyl(lower)alkyl or morpholinylcarbonyl(lower)alkyl;

[0072] piperidino which may have hydroxy(lower)alkyl or lower alkoxy;

[0073] morpholino which has 1 or 2 substituent(s) selected from thegroup consisting of ethyl, hydroxy(lower)alkyl, halo(lower)alkyl andlower alkoxy(lower)alkyl;

[0074] morpholino which has lower alkyl and lower alkoxy(lower)alkyl;

[0075] 3,5-dimethylmorpholino;

[0076] morpholinylamino which may have lower alkanoyl;

[0077] homomorpholinylamino; or

[0078] thiomorpholinylamino,

[0079] R⁸ is morpholino which may have lower alkyl or loweralkoxy(lower)alkyl,

[0080] R⁹ is pyrrolidino which may have lower alkoxy(lower)alkyl;

[0081] morpholino which may have 1 or 2 substituent(s) selected from thegroup consisting of ethyl, propyl, isopropyl, isobutyl,spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl,carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl andhalo (lower) alkyl;

[0082] morpholino which has methyl and lower alkoxy;

[0083] dimethylmorpholino; or homomorpholino which has halogen,

[0084] W₁, W₂, W₃ and W₄ are each a leaving group.

[0085] As to the starting compounds (II), (III), (IV), (V), (VI), (VII),(VIII), (IX) and (X), some of them are novel and can be prepared by theprocedures described in the Preparations and Examples mentioned later orsimilar manners thereto.

[0086] Suitable salts of the starting and object compounds areconventional non-toxic and pharmaceutically acceptable salt and includean acid addition salt such as an organic acid salt (e.g. acetate,trifluoroacetate, fumarate, maleate, tartrale, methanesulfonate,benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acidsalt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate,phosphate, etc.), or a salt with an amino acid (e.g. arginine, asparticacid, glutamic acid, etc.), or a metal salt such as an alkali metal salt(e.g. sodium salt, potassium salt, etc.) and an alkaline earth metalsalt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, anorganic base salt (e.g. trimethylamine salt, triethylamine salt,pyridine salt, picoline salt, dicyclohexylamine salt,N,N′-dibenzylethvlenediamine salt, etc.), or the like.

[0087] In the above and subsequent descriptions of the presentspecification, suitable examples and illustrations of the variousdefinitions which the present invention intends to include within thescope thereof are explained in detail as follows.

[0088] The term “lower” is intended to mean 1 to 6, preferably 1 to 4,carbon atom(s), unless otherwise indicated.

[0089] Suitable “lower alkylene” may include straight or branched onehaving 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene,propylene, tetramethylene, methylmethylene, methyltrimethylene,hexamethylene, and the like, in which the preferred one is methylene,ethylene, trimethylene or methylmethylene.

[0090] Suitable “lower alkenylene” may include straight or branched onehaving 2 to 6 carbon atom(s) such as vinylene, propenylene, 1-(or2-)butenylene, 1-(or 2- or 3-)pentenylene, 1-(or 2- or 3-)hexenylene,methylvinylene, ethylvinylene, 1-(or 2- or 3-)methylpropenylene, 1-(or2- or 3-)-ethylpropenylene, 1-(or 2- or 3- or 4-)methyl-1-(or2-)-butenylene, and the like.

[0091] Suitable “lower alkynylene” may include one having 2 to 6 carbonatoms, such as ethynylene, propynylene, butynylene, and the like, inwhich the preferred one is propynylene or butynylene.

[0092] Suitable “halogen” and “halogen” moiety in the terms “mono(or dior tri)halo(lower)alkyl”, “mono(or di or tri)halo(C₁-C₄)alkyl”, etc. mayinclude fluorine, chlorine, bromine and iodine.

[0093] Suitable “lower alkyl” and “lower alkyl” moiety in the terms“pyridyl(lower)alkylamino(lower)alkynyl”, “N-(loweralkyl)-N-[pyridyl(lower)alkyl]amino(lower)alkyl”, etc. may includestraight or branched one having 1 to 6 carbon atom(s), such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like,preferably one having 1 to 5 carbon atom(s).

[0094] Suitable “lower alkenyl” moiety in the terms“3-pyridyl(lower)alkenyl”, “saturated heterocyclic(lower)alkenyl”, etc.may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2-or 3- or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, methylvinyl,ethylvinyl, 1-(or 2- or 3-)methyl-1-(or 2-)propenyl, 1-(or 2- or3-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3- or 4-)methyl-1- (or 2- or3-)butenyl, and the like, in which more preferable example may be C₂-C₄alkenyl.

[0095] Suitable “lower alkynyl” moiety in the terms“pyridyl(lower)alkylamino(lower)alkynyl”, “(2-pyridyl)-(lower)alkynyl”,etc. may include ethynyl, 1-propynyl, propargyl, 1-methylpropargyl,1-(or 2- or 3-)butynyl, 1-(or 3-)methyl-2-butynyl, 1-(or3-)ethyl-2-butynyl, 1-(or 3-)propyl-2-butynyl, 1-(or3-)isopropyl-2-butynyl, 1-(or 2- or 3- or 4-)pentynyl, 1-(or 2- or 3- or4- or 5-)-hexynyl and the like, in which more preferable example may beC₂-C₅ alkynyl.

[0096] Suitable “aryl” may include phenyl, naphthyl, and the like, inwhich the preferred one is C₆-C₁₀ aryl and the most preferred one isphenyl or naphthyl.

[0097] Suitable “lower alkanoyl” and “lower alkanoyl” moiety in the term“lower alkanoyl(lower)alkoxy(lower)alkyl” may include formyl, acetyl,propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,2,2-dimethylpropanoyl, hexanoyl and the like.

[0098] Suitable “lower alkoxy” and “lower alkoxy” moiety in the terms“hydroxy(lower)alkoxy(lower)alkyl”, “loweralkanoyl(lower)alkoxy(lower)alkyl”, etc. may include methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy,t-pentyloxy, hexyloxy and the like.

[0099] Suitable “saturated heterocyclic” and “saturated heterocyclic”moiety in the terms “saturated heterocyclicimino(lower)alkyl”,“saturated heterocyclicaminocarbonyl(lower)alkyl”, etc. may include

[0100] saturated 3 to 8-membered (more preferably 5 to 7-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl,hexamethyleneimino, etc.;

[0101] saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, morpholinyl, homomorpholinyl, sydnonyl,etc.;

[0102] saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, thiomorpholinyl, etc.;

[0103] saturated heterobicycliLc group of the formula:

[0104] (wherein u, m and n are each integer of 1 to 6);

[0105] saturated heterobicyclic group of the formula:

[0106] (wherein q, r, s and t are each integer of 1 to 6); and the like.

[0107] Suitable “substituent” in the terms “aryl which may havesubstituent(s)”, “aryl or indolyl, each of which may havesubstituent(s)”, “pyridyl, thiazolyl, imidazolyl or pyrazolyl, each ofwhich may have substituent(s)” and “saturatedheterocyclicimino(lower)alkyl, saturatedheterocyclicaminocarbonyl(lower)alkyl or saturatedheterocyclic(lower)alkoxy(lower)alkyl, each of which may havesubstituent(s)” may include lower alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl,hexyl, etc.), cyclo(lower)alkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, etc.), lower alkylenedioxy (e.g.,methylenedioxy, ethylenedioxy, propylenedioxy, etc.), lower alkoxy(e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy,pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, etc.), loweralkoxylower)alkyl (e.g., methoxymethyl, ethoxymethyl, 1-methoxyethyl,2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, etc.), lower alkanoyl(e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, etc.), loweralkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propylcarbonyl,isopcopylcarbonyl, etc.), lower alkenyl (e.g., vinyl, 1-propenyl, allyl,1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or3 or 4 or 5-hexenyl, etc.), lower alkynyl (e.g., ethynyl, 1-propynyl,propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.), mono(or di ortri)halo(lower)alkyl (e.g., fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,bromomiezhyl, dibromomethyl, tribromomethyl, 1 or 2-fluoroethyl, 1 or2-bromoethyl, 1 or 2-chloroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,etc.), halogen (e.g., chlorine, bromine, fluorine and iodine), carboxy,protected carboxy, hydroxy, protected hydroxy, aryl (e.g., phenyl,naphthyl, etc.), ar(lower)alkyyl such as phenyl(lower)alkyl (e.g.,benzyl, phenethyl, phenylpropyl, etc.), carboxy(lower)alkyl whereinlower alkyl moiety can be referred to the ones as exemplified above,protected carboxy(lower)alkyl wherein lower alkyl moiety can be referredto the ones as exemplirfied above, nitro, amino, protected amino, loweralkylamino (e.g. methylamino, ethylamino, isopropylamino, etc.),di(lower)alkylamino (e.g., dimethylamino, diethylamino,duisopropylamino, ethylmethylamino, isopropylmethylamino,ethylisopropylamino, etc.), hydroxy, hydroxy(lower)alkyl (e.g.hydroxymethyl, hydroxyethyl, etc.), protected hydroxy(lower)alkyl, acyl,cyano, oxo, mercapto, lower alkylthio (e.g., methylthio, ethylthio,propylthio, isoprovlithio, butylthio, etc.), lower alkylsulfinyl (e.g.,methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl,butylsulfinyl, etc.), imino, morpholinyl (e.g., 2-morpholinyl,3-morpholinyl, morpholino), bivalent group of the formula:

[0108] carboxy(lower)alkyl (e.g., carboxrmethyl, carboxyethyl,carboxypropyl, etc.), lower alkoxycarbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl,tert-pentyloxycarbonyl, hexyloxycarbonyl, etc.), spirocyclo(lower)alkyl(e.g., spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, etc.),ar(lower)alkoxycarbonyl(lower)alkyl (e.g., benzyloxycarbonylmethyl,benzyloxycarbonylethyl, benzyloxycarbonylpropyi, etc.), pyridyl(lower)alkyl (e.g., pyridylmethyl, pyridylethyl, etc.), carbamoyl, loweralkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), di(loweralkyl)carbamoyl (e.g dimethylcarbamoyl, diethylcarbamoyl, etc.), and thelike.

[0109] Suitable “leaving group” may include lower alkoxy (e.g. methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy,etc.), aryloxy (e.g. phenoxy, naphthoxy, etc.), an acid residue or thelike.

[0110] Suitable “acid residue” may be halogen (e.g. chlorine, bromine,iodine, etc.), sulfonyloxy (e.g. methanesulfonyloxy, phenylsulfonyloxy,mesitylenesulfonyloxy, toluenesulfonyloxy, etc.) or the like.

[0111] Preferred embodiments of the object compound (I) are as follows:

[0112] Y is lower alkylene (more preferably C₁-C₄ alkylene, mostpreferably methylene);

[0113] R¹ is aryl (more preferably C₆-C₁₀ aryl, most preferably phenyl)which may have 1 to 3 (more preferably 1 or 2, most preferably 2)substituent(s) [more preferably substituent selected from the groupconsisting of mono(or di or tri)halo(lower)alkyl (more preferablytrihalo(lower)alkyl, most preferably trifluoromethyl), halogen (morepreferably chlorine), lower alkylamino (more preferably C₁-C₄alkylamino, most preferably methylamino), di-(lower)alkylamino (morepreferably di(C₁-C₄)alkylamino, most preferably dimethylamino) andnitro];

[0114] R² is aryl (more preferably C₆-C₁₀ aryl, most preferably phenylor naphthyl) or indolyl, each of which may have 1 to 3 (more preferably1 or 2) substituent(s) [more preferably substituent selected from thegroup consisting of lower alkyl (more preferably C₁-C₄ alkyl, mostpreferably methyl), mono(or di or tri)halo(lower)alkyl (more preferablymono(or di or tri)halo(C₁-C₄)alkyl, most preferably trifluoromethyl),lower alkylenedioxy (more preferably C₁-C₄ alkylenedioxy, mostpreferably methylenedioxy or ethylenedioxy), hydroxy,hydroxy(lower)alkyl (more preferably hydroxy(C₁-C₄)alkyl, mostpreferably hydroxymethyl), lower alkoxy (more preferably C₁-C₄ alkoxy,most preferably methoxy), lower alkylamino (more preferably C₁-C₄alkylamino, most preferably methylamino) and di(lower)alkylamino (morepreferably di(C₁-C₄)alkylamino, most preferably dimethylamino)];

[0115] R³ is hydrogen; and

[0116] R⁴ is pyridyl(lower)alkylamino(lower)alkynyl (more preferablypyridyl(C₁-C₄)alkylamino(C₂-C₄)alkynyl, most preferably4-[(3-pyridylmethyl)amino]-2-butynyl);

[0117] N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino(lower)alkyl [morepreferably N-(C₁-C₄ alkyl)-N-[pyridyl(C₁-C₄)-alkyl]amino(C₁-C₄)alkyl,most preferably 2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl];

[0118] hydroxy(lower)alkoxy(lower)-alkyl (more preferablyhydroxy(C₁-C₄)alkoxy(C₁-C₄)alkyl, most preferably (hydroxyethoxy)ethyl);

[0119] lower alkanoyl(lower)alkoxy(lower)alkyl (more preferably C₁-C₄alkanoyl(C₁-C₄)alkoxy(C₁-C₄)alkyl, most preferably formylmethoxyethyl);

[0120] phenyl(lower)alkyl (more preferably phenyl(C₁-C₄)alkyl, mostpreferably benzyl) which has hydroxy(lower)alkyl (more preferablyhydorxy(C₁-C₄)alkyl, most preferably hydroxymethyl) ormorpholinyl(lower)alkyl (more preferably morpholinyl(C₁-C₄)alkyl, mostpreferably morpholinomethyl) [more preferably α-(hydroxymethyl)-benzylor α-(morpholinomethyl)benzyl];

[0121] ar(lower)alkoxycarbonyl (more preferably (C₆-C₁₀aryl)(C₁-C₄)alkoxycarbonyl, most preferably phenylmethoxycarbonyl);

[0122] (2-pyridyl)(lower)alkyl (more preferably(2-pyridyl)-(C₁-C₄)alkyl, more preferably (2-pyridyl)propyl or(2-pyridyl)butyl) which may have 1 to 3 (more preferably 1 or 2)substituent(s) selected from the group consisting of lower alkyl (morepreferably C₁-C₄ alkyl, most preferably methyl), lower alkoxy (morepreferably C₁-C₄ alkoxy, most preferably methoxy), lower alkoxycarbonyl(more preferably C₁-C₄ alkoxycarbonyl, most preferably methoxycarbonyl),mono(or di or tri)halo(lower)alkyl (more preferablytrihalo(C₁-C₄)-alkyl, most preferably trifluoromethyl) and halogen (morepreferably fluorine));

[0123] (3-pyridyl)propyl (more preferably 3-(3-pyridyl)propyl) which mayhave lower alkoxy (more preferably C₁-C₄ alkoxy, most preferablymethoxy);

[0124] (3-pyridyl)butyl (more preferably 4-(3-pyridyl)butyl);pyridyl(lower)alkenyl (more preferably pyridyl(C₂-C₄)-alkenyl, mostpreferably 3-(3-pyridyl)-2-propenyl);

[0125] (2-pyridyl)(lower)alkynyl (more preferably(2-pyridyl)-(C₂-C₄)alkynyl, most preferably 3-(2-pyridyl)-2-propynyl or4-(2-pyridyl)-3-butynyl) which may have 1 to 3 (more preferably 1 or 2)substituent(s) selected from the group consisting of lower alkyl (morepreferably C₁-C₄ alkyl, most preferably methyl), lower alkoxy (morepreferably C₁-C₄ alkoxy, most preferably methoxy), lower alkoxycarbonyl(more preferably C₁-C₄ alkoxycarbonyl, most preferably methoxycarbonyl),mono (or di or tri)-halo(lower)alkyl (more preferablytrihalo(C₁-C₄)alkyl, most preferably trifluoromethyl) and halogen (morepreferably fluorine);

[0126] (3-pyridyl)(lower)alkynyl (more preferably(3-pyridyl)-(C₂-C₄)alkynyl, most preferably 3-(3-pyridyl)-2-propynyl or4-(3-pyridyl)-3-butynyl) which may have lower alkoxy (more preferablyC₁-C₄ alkoxy, most preferably methoxy) or amino;

[0127] pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which mayhave 1 to 3 (more preferably 1 or 2) substituent(s) [more preferablysubstituent selected from the group consisting of lower alkyl (morepreferably C₁-C₄ alkyl, most preferably methyl or isopropyl),ar(lower)alkyl (more preferably phenyl-(C₁-C₄)alkyl, most preferablybenzyl) and pyridyl-(lower)alkyl (more preferably pyridyl(C₁-C₄)alkyl,most preferably pyridylmethyl)];

[0128] imidazolyl(lower)alkyl (more preferably imidazolyl-(C₁-C₄)alkyl,most preferably 3-(1H-imidazol-4-yl)-propyl) which may have 1 or 2substituent(s) selected from the group consisting of lower alkyl (morepreferably C₁-C₄ alkyl, most preferably methyl or isopropyl), loweralkynyl (more preferably C₂-C₅ alkynyl, most preferably propargyl),ar(lower)alkyl (more preferably phenyl(C₁-C₄)alkyl, most preferablybenzyl), pyridyl(lower)alkyl (more preferably pyridyl(C₁-C₄)alkyl mostpreferably pyridylmethyl), mono(or di or tri)halo(lower)alkyl (morepreferably trihalo(C₁-C₄)alkyl, most preferably trifluoromethyl) andhalogen (more preferably fluorine);

[0129] pyrazolyl(lower)alkyl (more preferably pyrazolyl(C₁-C₄)-alkyl,most preferably (1H-pyrazol-4-yl)methyl or 3-(1H-pyrazol-1-yl)propyl)which may have hydroxy(lower)alkyl (more preferably hydroxy(C₁-C₄)alkyl,most preferably 2-hydroxyethyl), carboxy(lower)alkyl (more preferablycarboxy(C₁-C₄)alkyl, most preferably carboxymethyl), loweralkoxycarbonyl(lower)alkyl (more preferably C₁-C₄alkoxycarbonyl(C₁-C₄)alkyl, most preferably tert-butoxycarbonylmethyl),morpholinyl(lower)alkyl (more preferably morpholinyl(C₁-C₄)alkyl, mostpreferably 2-morpholinoethyl) or morpholinylcarbonyl(lower)alkyl (morepreferably morpholinylcarbonyl(C₁-C₄)alkyl, most preferablymorpholinocarbonylmethyl);

[0130] thiazolyl(lower)alkyl (more preferably thiazoly(C₁-C₄)-alkyl,most preferably 4-thiazolymethyl) which may have lower alkyl (morepreferably C₁-C₄ alkyl, most preferably methyl);

[0131] piperidyl(lower)alkyl (more preferably piperidyl(C₁-C₄)-alkyl,most preferably piperidylethyl) which may have hydroxy(lower)alkyl (morepreferably hydroxy(C₁-C₄)-alkyl, most preferably hydroxymethyl) or loweralkoxy (more preferably C₁-C₄ alkoxy, most preferably ethoxy);

[0132] morpholinyl(lower)alkyl (more preferablymorpholinyl-(C₁-C₄)alkyl, most preferably morpholinylethyl ormorpholinylpropyl) which has 1 or 2 substituent(s) selected from thegroup consisting of ethyl, hydroxy-(lower)alkyl (more preferablyhydroxy(C₁-C₄)alkyl, most preferably hydroxymethyl), halo(lower)alkyl(more preferably halo(C₁-C₄)alkyl, most preferably fluoromethyl) andlower alkoxy(lower)alkyl (more preferably C₁-C₄ alkoxy(C₁-C₄)alkyl, mostpreferably methoxymethyl);

[0133] morpholinyl(lower)alkyl (more preferablymorpholinyl-(C₁-C₄)alkyl, most preferably morpholinoethyl ormorpholinopropyl) which has lower alkyl (more preferably C₁-C₄ alkyl,most preferably methyl) and lower alkoxy(lower)alkyl (more preferablyC₁-C₄ alkoxy-(C₁-C₄)alkyl, most preferably methoxymethyl);

[0134] (3,5-dimethylmorpholino)(lower)alkyl (more preferably(3,5-dimethylmorpholino) (C₁-C₄)alkyl, most preferably(3,5-dimethylmorpholino)ethyl);

[0135] morpholino(lower)alkenyl (more preferablymorpholino-(C₂-C₄)alkenyl, most preferably 4-morpholino-2-butenyl) whichmay have lower alkyl (more preferably C₁-C₄ alkyl, most preferablyisopropyl) or lower alkoxy(lower)alkyl (more preferably C₁-C₄alkoxy(C₁-C₄)alkyl, most preferably methoxymethyl);

[0136] (2- or 3-morpholinyl)(lower)alkenyl (more preferably (2- or3-morpholinyl)(C₂-C₄)alkenyl, most preferably 3-(2- or3-morpholinyl)-2-propenyl) which may have lower alkoxycarbonyl (morepreferably C₁-C₄ alkoxycarbonyl, most preferably tert-butoxycarbonyl);

[0137] pyrrolidinyl(lower)alkynyl (more preferably pyrrolidinyl(C₂-C₄)alkynyl, most preferably 4-pyrrolidino-2-butynyl) which may havelower alkoxy(lower)alkyl (more preferably c₁-C₄ alkoxy(C₁-C₄)alkyl, mostpreferably methoxymethyl);

[0138] morpholinyl(lower)alkynyl (more preferablymorpholinyl-(C₂-C₄)alkynyl, most preferably 4-morpholino-2-butynyl or3-(3-morpholinyl)-2-propynyl) which may have 1 or 2 substituent(s)selected from the group consisting of ethyl, propyl, isopropyl,isobutyl, spirocyclo(lower)alkyl (more preferablyspirocyclo-(C₃-C₆)alkyl, most preferably spirocyclopropyl), loweralkoxy(lower)alkyl (more preferably C₁-C₄ alkoxy(C₁-C₄)-alkyl, mostpreferably methoxymethyl or ethoxymethyl), hydroxy(lower)alkyl (morepreferably hydroxy(C₁-C₄)-alkyl, most preferably hydroxymethyl),carboxy(lower)-alkyl (more preferably carboxy(C₁-C₄)alkyl, mostpreferably carboxymethyl), di(lower)alkylcarbamoyl (more preferablydi(C₁-C₄)alkylcarbamoyl, most preferably dimethylcarbamoyl), loweralkoxycarbonyl (more preferably C₁-C₄ alkoxycarbonyl, most preferablyethoxycarbonyl) and halo(lower)alkyl (more preferably halo(C₁-C₄)alkyl,most preferably fluoromethyl);

[0139] morpholinyl(lower)alkynyl (more preferablymorpholinyl-(C₂-C₄)alkynyl, most preferably 4-morpholino-2-butynyl)which has methyl and lower alkoxy(lower)alkyl (more preferably C₁-C₄alkoxy(C₁-C₄)alkyl, most preferably methoxymethyl);

[0140] (dimethylmorpholino)(lower)alkynyl (more preferably(dimethylmorpholino)(C₂-C₄)alkynyl, most preferably4-(3,3-dimethylmorpholino)-2-butynyl,4-(2,6-dimethylmorpholino)-2-butynyl or4-(3,5-dimethylmorpholino)-2-butynyl);

[0141] homomorpholinyl(lower)alkynyl (more preferablyhomomorpholinyl(C₂-C₄)alkynyl, most preferably4-homomorpholino-2-butynyl) which may have halogen (more preferablyfluorine);

[0142] morpholinylaminopropyl (more preferably3-(morpholinoamino)propyl) which may have lower alkanoyl (morepreferably C₁-C₄ alkanoyl, most preferably formyl);

[0143] thiomorpholinyl(lower)alkynyl (more preferablythiomorpholinyl(C₂-C₄)alkynyl, most preferably4-thiomorpholino-2-butynyl);

[0144] homomorpholinylamino(lower)alkyl (more preferablyhomomorpholinylamino(C₁-C₄)alkyl, more preferablyhomomorpholinoaminopropyl);

[0145] thiomorpholinylamino(lower)alkyl (more preferablythiomorpholinylamino(C₁-C₄)alkyl, more preferablythiomorpholinoaminopropyl); or

[0146] saturated heterocyclicimino(lower)alkyl (more preferablysaturated heterocyclicimino(C₁-C₄)alkyl, most preferably saturatedheterocycliciminoethyl), saturated heterocyclicaminocarbonyl(lower)alkyl(more preferably saturated heterocyclicaminocarbonyl(C₁-C₄)-alkyl, mostpreferably saturated heterocyclicaminocarbonylmethyl) or saturatedheterocyclic(lower)alkoxy(lower)alkyl (more preferably saturatedheterocyclic(C₁-C₄)alkoxy(C₁-C₄)alkyl, most preferably saturatedheterocyclicethoxyethyl) [wherein “saturated heterocyclic” moiety issaturated 3 to 8-membered (more preferably 5 to 7-membered)heteromonocyclic group containing 1 to 4 (more preferably 1 or 2)nitrogen atom(s) (more preferably pyrrolidinyl, piperidyl orpiperazinyl);

[0147] saturated 3 to 8-membered (more preferably 5 to 7-membered)heteromonocyclic group containing 1 or 2 (more preferably 1) oxygenatom(s) and 1 to 3 (more preferably 1) nitrogen atom(s) (more preferablymorpholinyl or homomorpholinyl);

[0148] saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 (more preferably 1) sulfuratom(s) and 1 to 3 (more preferably 1) nitrogen atom(s) (more preferablythiomorpholinyl); or saturated heterocyclic group of the formula

[0149] (wherein q, r, s and t are each as defined above)

[0150] (more preferably 3-azabicyclo[3.2.2]non-3-yl)], each of which mayhave 1 to 3 (more preferably 1 or 2) suitable substituent(s) [morepreferably substituent selected from the group consisting ofcyclo(lower)alkyl (more preferably cyclohexyl), lower alkanoyl (morepreferably C₁-C₄ alkanoyl, most preferably formyl), lower alkyl (morepreferably C₁-C₄ alkyl, most preferably methyl, ethyl, isopropyl orisobutyl), mono(or di or tri)halo(lower)alkyl (more preferablymonohalo(C₁-C₄)-alkyl or trihalo(C₁-C₄)alkyl, most preferablyfluoromethyl or trifluoromethyl), lower alkoxy (more preferably C₁-C₄alkoxy, most preferably methoxy), lower alkoxy(lower)alkyl (morepreferably C₁-C₄ alkoxy(C₁-C₄)-alkyl, most preferably methoxymethyl),halogen (more preferably chlorine or fluorine), aryl (more preferablyphenyl), cyano, oxo, bivalent group of the formula:

[0151] carboxy(lower)alkyl (more preferably carboxy(C₁-C₄)-alkyl, mostpreferably carboxypropyl), lower alkoxycarbonyl (more preferably C₁-C₄alkoxycarbonyl, most preferably tert-butoxycarbonyl),spirocyclo(lower)alkyl (more preferably spirocyclo-(C₁-C₄)alkyl, mostpreferably spirocyclopropyl), ar(lower)alkoxycarbonyl(lower)alkyl (morepreferably benzyloxycarbonyl(C₁-C₄)alkyl, most preferablybenzyloxycarbonylpropyl), hydroxy(lower)alkyl (more preferablyhydroxy(C₁-C₄)alkyl, most preferably hydroxymethyl), carbamoyl, loweralkylcarbamoyl (more preferably C₁-C₄ alkylcarbamoyl, most preferablymethylcarbamoyl) and di(lower alkyl)carbamoyl (more preferably di(C₁-C₄alkyl)carbamoyl, most preferably dimethylcarbamoyl)].

[0152] More preferred embodiments of the object compound (I) are asfollows:

[0153] Y is lower alkylene (more preferably C₁-C₄ alkylene, mostpreferably methylene);

[0154] R¹ is phenyl which may have 1 or 2 substituent(s) selected fromthe group consisting of mono(or di or tri)halo-(lower)alkyl, halogen(more preferably chlorine), lower alkylamino, di(lower)alkylamino andnitro [more preferably bis(trihalo(lower)alkyl)phenyl or dichlorophenyl,most preferably bis(trifluoromethyl)phenyl];

[0155] R² is phenyl which may have 1 or 2 substituent(s) selected fromthe group consisting of lower alkyl, mono(or di or tri)halo(lower)alkyl,lower alkylenedioxy, hydroxy, hydroxy(lower)alkyl, lower alkoxy, loweralkylamino and di(lower)alkylamino [more preferably di(loweralkyl)phenyl or [trihalo(lower)alkyl]phenyl, most preferablydimethylphenyl or (trifluoromethyl)phenyl], naphthyl or indolyl;

[0156] R³ is hydrogen; and

[0157] R⁴ is pyridyl(lower)alkylamino(lower)alkynyl (more preferablypyridyl(C₁-C₄)alkylamino(C₂-C₄)alkynyl, most preferably4-[(3-pyridylmethyl)amino]-2-butynyl) or (2-pyridyl)(lower)alkyl (morepreferably (2-pyridyl)-(C₁-C₄)alkyl, more preferably (2-pyridyl)propylor (2-pyridyl)butyl, most preferably 3-(2-pyridyl)propyl.

[0158] Another more preferred embodiments of the object compound (I) areas follows:

[0159] Y is lower alkylene,

[0160] R¹ is C₆-C₁₀ aryl which may have 1 or 2 mono(or di ortri)halo(lower)alkyl,

[0161] R² is C₆-C₁₀ aryl or indolyl, each of which may have 1 to 3substituent(s) selected from the group consisting of lower alkyl,mono(or di or tri)halo-(lower)alkyl, lower alkylenedioxy, hydroxy,hydroxy(lower)alkyl, lower alkoxy, lower alkylamino anddi(lower)alkylamino,

[0162] R³ is hydrogen, and

[0163] R⁴ is pyridyl(lower)alkylamino(lower)alkynyl;

[0164] (2-pyridyl)propyl which may have 1 to 3 substituent(s) selectedfrom the group consisting of lower alkyl, lower alkoxy, mono(or di ortri)halo(lower)alkyl and halogen;

[0165] pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which mayhave 1 or 2 substituent(s) selected from the group consisting of loweralkyl, ar(lower)alkyl and pyridyl(lower)alkyl;

[0166] imidazolyl(lower)alkyl which has 1 or 2 substituent(s) selectedfrom the group consisting of lower alkynyl, ar(lower)alkyl,pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen;

[0167] (2-methyl-1H-imidazol-4-yl)(lower)alkyl which has 1 or 2substituent(s) selected from the group consisting of isopropyl, loweralkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di ortri)halo(lower)alkyl and halogen;

[0168] (5-methyl-1H-imidazol-4-yl)(lower)alkyl which has 1 or 2substituent(s) selected from the group consisting of isopropyl, loweralkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di ortri)halo(lower)alkyl and halogen;

[0169] piperidyl(lower)alkyl which may have hydroxy(lower)alkyl or loweralkoxy;

[0170] morpholinyl(lower)alkyl which has 1 or 2 substituent(s) selectedfrom the group consisting of ethyl, hydroxy(lower)alkyl,halo(lower)alkyl and lower alkoxy-(lower) alkyl;

[0171] morpholinyl(lower)alkyl which has lower alkyl and loweralkoxy(lower)alkyl;

[0172] (3,5-dimethylmorpholino)(lower)alkyl;

[0173] morpholino(lower)alkenyl which may have lower alkyl or loweralkoxy(lower)alkyl;

[0174] (2- or 3-morpholinyl)(lower)alkenyl which may have loweralkoxycarbonyl;

[0175] pyrrolidinyl(lower)alkynyl which may have loweralkoxy(lower)alkyl;

[0176] morpholinyl(lower)alkynyl which may have 1 or 2 substituent(s)selected from the group consisting of ethyl, propyl, isopropyl,isobutyl, spirocyclo(lower)-alkyl, lower alkoxy(lower)alkyl,hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl,lower alkoxycarbonyl and halo(lower)alkyl;

[0177] morpholinyl(lower)alkynyl which has methyl and loweralkoxy(lower)alkyl;

[0178] (dimethylmorpholino)(lower)alkynyl; or

[0179] homomorpholinyl(lower)alkynyl which may have halogen.

[0180] The Processes 1 to 6 for preparing the object compound (I) of thepresent invention are explained in detail in the following.

[0181] Process 1

[0182] The object compound (I) or a salt thereof can be prepared byreacting the compound (II) or its reactive derivative at the imino groupor a salt thereof with the compound (IV) or a salt thereof.

[0183] Suitable reactive derivative at the imino group of the compound(II) may include Schiff's base type imino or its tautomeric enamine typeisomer formed by the reaction of the compound (II) with a carbonylcompound such as aldehyde, ketone or the like; a silyl derivative formedby the reaction of the compound (II) with a silyl compound such asbis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide,bis(trimethylsilyl)urea or the like; a derivative formed by reaction ofthe compound (II) with phosphorus trichloride or phosgene and the like.

[0184] The reaction is usually carried out in a conventional solventsuch as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxene,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvents may also be used in a mixture with water.

[0185] The reaction may also be carried out in the presence of aninorganic or organic base such as alkali metal carbonate, alkali metalbicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, or the like.

[0186] The reaction temperature is not critical, and the reaction isusually carried out under cooling to heating.

[0187] Process 2

[0188] The object compound (Ib) or a salt thereof can be prepared bysubjecting the compound (Ia) or a salt thereof to a reduction reaction.

[0189] The reaction can be carried out in the manner disclosed inExample 3 mentioned later or similar manners thereto.

[0190] Process 3

[0191] The object compound (Ic) or a salt thereof can be prepared byreacting the compound (III) or its reactive derivative at the carboxygroup or a salt thereof with the compound (V) or its reactive derivativeat the amino group or a salt thereof.

[0192] Suitable reactive derivative at the carboxy group of the compound(III) may include an acid halide, an acid anhydride, an activated amide,an activated ester, and the like. The suitable example of the reactivederivative may be an acid chloride; an acid azide; a mixed acidanhydride with an acid such as substituted phosphoric acid [e.g.dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.],dialkylphosphorous acid, lower alkanesulfonic acid [e.g. methanesulfonicacid, ethanesulfonic acid, etc.], sulfurous acid, thiosulfuric acid,sulfuric acid, aliphatic carboxylic acid [e.g. acetic acid, propionicacid, butyric acid, isobutyric acid, pivalic acid, valeric acid,isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] oraromaticcarboxylic acid [e.g. benzoic acid, etc.]; a symmetrical andanhydride; an activated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g.cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl[(CH₃)₂N⁺═CH—] ester, vinyl ester, propargyl ester, p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester,etc.], or an ester with a N-hydroxy compound [e.g.N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,etc.], and the like. These reactive derivatives can optionally beselected from them according to the kind of the compound (III) to beused.

[0193] The reaction is usually carried out in a conventional solventsuch as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvents may also be used in a mixture with water.

[0194] In this reaction, when the compound (III) is used in a free acidform or a salt thereof, the reaction is preferably carried out in thepresence of a conventional condensing agent such asN,N′-dichlorohexylcarbodiimide;N-cyclohexyl-N′-morpholinoethylcarbodiimide;N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide;N,N′-diethylcarbodiimide; N,N′-diisopropylcarbodiimide;N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide;pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; diphenyl phosphorylazide; thienyl chloride;oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate,isopropyl chloroformate, etc.]; triphenylphosphine;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)-isoxazolium hydroxide intramolecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole;2-chloro-1-methylpyridinium iodide;1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; so-calledvilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorusoxychloride, etc.; or the like.

[0195] The reaction may also be carried out in the presence of aninorganic or organic base such as alkali metal carbonate, alkali metalbicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, or the like.

[0196] The reaction temperature is not critical, and the reaction isusually carried out under cooling to warming.

[0197] Process 4

[0198] The object compound (Id) or a salt thereof can be prepared byreacting the compound (VI) or a salt thereof with the compound (VII) ora salt thereof.

[0199] The reaction can be carried out in the manner disclosed inExample 30 mentioned later or similar manners thereto.

[0200] Process 5

[0201] The object compound (Ie) or a salt thereof can be prepared byreacting the compound (VIII) or a salt thereof with the compound (IX) ora salt thereof.

[0202] The reaction can be carried out in the manner disclosed inExample 35 mentioned later or similar manners thereto.

[0203] Process 6

[0204] The object compound (If) or a salt thereof can be prepared byreacting the compound (X) or a salt thereof with the compound (XI) or asalt thereof.

[0205] The reaction can be carried out in the manner disclosed inExample 8 mentioned later or similar manners thereto.

[0206] The object compound (I) and a pharmaceutically acceptable saltthereof have pharmacological activities such as Tachykinin antagonism,especially Substance P antagonism, Neurokinin A antagonism or NeurokininB antagonism, and therefore are useful for treating or preventingTachykinin-mediated diseases, particularly Substance P-mediateddiseases, for example, respiratory diseases such as asthma, bronchitis(e.g. chronic bronchitis, acute bronchitis and diffuse panbronchiolitis,etc.), rhinitis, couph, expectoration, and the like; ophthalmic diseasessuch as conjunctivitis, vernal conjunctivitis, and the like; cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis, and the like; inflammatory diseases such asrheumatoid arthritis, osteoarthritis, and the like; pains or aches (e.g.migraine, headache, cluster headache, toothache, cancerous pain, backpain, neuralgia, etc.); and the like.

[0207] Further, it is expected that the object compound (I) and apharmaceutically acceptable salt thereof of the present invention areuseful for treating or preventing ophthalmic diseases such as glaucoma,uveitis, and the like; gastrointestinal diseases such as ulcer,ulcerative colitis, irritable bowel syndrome, food allergy, and thelike; inflammatory diseases such as nephritis, and the like; circulatorydiseases such as hypertension, angina pectoris, cardiac failure,thrombosis, Raynaud's disease, and the like; epilepsy; spasticparalysis; pollakiuria; cystitis; bladder detrusor hyperreflexia;urinary incontinence; Parkinson diseases; dementia; AIDS relateddementia; Alzheimer's diseases; Down's syndrome; Huntington's chorea;carcinoid syndrome; disorders related to immune enhancement orsuppression; disorders caused by Helicobacter pylori or another spiralurease-positive gram-negative bacterium; sunburn; angiogenesis ordiseases caused by angiogenesis; and the like.

[0208] It is furthermore expected that the object compound (I) and apharmaceutically acceptable salt thereof of the present invention areuseful for treating or preventing chronic obstructive pulmonarydiseases, particularly chronic pulmonary emphysema; iritis;proliferative vitreoretinopathy; psoriasis; inflammatory intestinaldiseases, particularly Crohn's diseases; hepatitis; superficial pain oncongelation, burn, herpes zoster or diabetic neuropathy; tenalgiaattended to hyperlipidemia; postoperative neuroma, particularly ofmastectomy; vulvar vestibulitis; hemodialysis-associated itching; lichenplanus; laryngopharyngitis; bronchiectasis; coniosis; whooping cough;pulmonary tuberculosis; cystic fibrosis; emesis (e.g. nausea, retching,vomiting, acute emesis, delayed emesis, anticipatory emesis, postoperative nausea and vomiting (PONV), acute and/or delayed emesisinduced by drugs such as cancer chemotherapeutic agents, etc.); mentaldiseases, particularly anxiety, depression, dysthymic disorders andschizophrenia; demyelinating diseases such as multiple sclerosis andamyotrophic lateral sclerosis; attenuation of morphine withdrawal;oedema, such as oedema caused by thermal injury; small cell carcinomas,particularly small cell lung cancer (SCLC); hypersensitivity disorderssuch as poison ivy; fibrosing and collagen diseases such as sclerodermaand eosinophilic fascioliasis; reflex sympathetic dystrophy such asshoulder/hand syndrome; addiction disorders such as alcoholism; stressrelated somatic disorders; rheumatic diseases such as fibrositis; andthe like.

[0209] Furthermore, the object compound (I) and a pharmaceuticallyacceptable salt thereof of the present invention are Central NervousSystem (CNS) penetrant.

[0210] For therapeutic purpose, the compound (I) and a pharmaceuticallyacceptable salt thereof of the present invention can be used in a formof pharmaceutical preparation containing one of said compound, as anactive ingredient, in admixture with a pharmaceutically acceptablecarrier such as an organic or inorganic solid or liquid excipientsuitable for oral, parenteral, external including topical, enternal,intravenous, intramuscular, inhalant, nasal, intraarticular,intraspinal, transtracheal or transocular administration. Thepharmaceutical preparations may be solid, semi-solid or solutions suchas capsules, tablets, pellets, dragees, powders, granules,suppositories, ointments, creams, lotions, inhalants, injections,cataplasms, gels, tapes, eye drops, solution, syrups, aerosols,suspension, emulsion, or the like. If desired, there may be included inthese preparations, auxiliary substances, stabilizing agents, wetting oremulsifying agents, buffers and other commonly used additives.

[0211] While the dosage of the compound (I) will vary depending upon theage and condition of a patient, an average single dose of about 0.1 mg,1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound(I) may be effective for treating Tachykinin-mediated diseases such asasthma and the like. In general, amounts between 0.1 mg/body and about1,000 mg/body may be administered per day.

[0212] In order to show the utility of the object compound (I) and apharmaceutically acceptable salt thereof, the pharmacological test dataof some representative compounds of the present invention is shown inthe following.

[0213] A. Evaluation of NK₁ Antagonist Transport Efficiency to theCental Nervous System Using a h-NK₁ Receptor Binding Assay

[0214] [I] Test Method

[0215] (1) Administration of Test Compound and Extraction of theCompound From Brain

[0216] Male SD rats were given an i.v. injection of a solutioncontaining a test compound (1 mg/kg). 5 Min later the animals wereanesthetized by ether, bled and perfused through the aorta ascendenswith 20 ml of saline. The brain was rapidly removed, weighed andhomogenized in 4 vol. ice-cold distilled water by using Polytoron(KINEMATICA). To extract the test compound, 500 μl of the homogenate,100 μl of methanol, 500 μl of 0.1 N NaOH and 4 ml of ethyl acetate weremixed by shaking for 10 min at room temperature. The organic phase (2.5ml) was recovered by centrifugation at 3,000 rpm for 10 min, dried anddissolved in dimethyl sulfoxide.

[0217] (2) h-NK₁ Receptor Binding Assay

[0218] (a) Crude CHO Cell Membrane Preparation

[0219] CHO cells permanently expressing h-NK₁ receptors were harvestedand homogenized with a Dounce homogenizer at 4° C. in a buffer (0.25 Msucrose, 25 mM Tris-HCl (pH 7.4), 10 mM MgCl₂, 1 mM EDTA, 5 μg/mlp-APMSF). The homogenate was centrifuged (500×g, 10 min), and the pelletwas resuspended in the same buffer, homogenized, and centrifuged. Thetwo supernatants were combined and centrifuged (100,000×g, 1 hour). Thecrude cell membranes thus isolated were resuspended in a buffer (25 mMTris-HCl (pH 7.4), 10 mM MgCl₂, 1 mMN EDTA, 5 μg/ml p-APMSF) and storedat −80° C. until use.

[0220] (b) ¹²⁵I-BH-Substance P Binding to the Prepared Membrane

[0221] Cell membranes (6 μg/ml) were incubated with ¹²⁵I-BH-Substance P(0.1 nM) with or without the extracted compounds in 0.25 ml of a medium(50 mM Tris-HCl (pH 7.4), 5 mM MnCl₂, 20 μg/ml chymostatin, 40 μg/mlbacitracin, 4 μg/ml leupeptin, 5 μg/ml p-APMSF, 200 μg/ml BSA) at 22° C.for 90 min. At the end of the incubation period, the contents werequickly filtered through a Blue Mat 11740 filter (pretreated with 0.1%polyethylenimine for 3 hours prior to use) by using SKATRON CellHarvester. The filter was then washed with a washing buffer (50 mMNTris-HCl (pH 7.4), 5 mM MnCl₂). The radioactivity was counted by usingan auto gamma counter (Packard RIASTAR 5420A) . All data presented arespecific binding defined as that displaceable by 3 μM unlabeledSubstance P.

[0222] [II] Test Result

[0223] All of the following Test Compounds showed more than 80%inhibition rate of ¹²⁵I-BH-Substance F binding to h-NK₁ receptors at thedose of 1 mg/kg.

[0224] Test Compounds: The object compounds of the Examples 1-(1),5-(2), 6-(1), 15, 16-(2), 171, 18, 22, 29, 30, 38, 40, 45, 56-(2), 68,70-(1), 70-(2), 71-(1), 71-(3), 71-(5), 71-(6), 73-(2), 73-(3), 76-(1),76-(3), 77, 78-(3), 78-(4), 79-(1), 79-(2), 80-(1), 80-(2), 80-(3),80-(4). 80- (6), 80-(7), 81-(1) , 81-(2), 81-(3), 81-(4), 81-(5),81-(7), 81-(10), 82, 83-(2), 84, 85-(3), 89-(1), 89-(2), 90-(2), 90-(3),90-(4), 90-(5) and 90-(6)

[0225] B. Emesis in the Ferret

[0226] [I] Test Method

[0227] Individually housed adult male ferrets (Marshall Farms, 1.4 to2.2 kg) were given an i.v. injection of a solution contatining a testcompound. 30 Min later the emetic responses (retching and vomiting) wereinduced by administration of intra-gastric copper sulfate (40 mg/kg/ml)and observed for the next 30 min. The timing and number of retches andvomits observed were recorded for each animal. An individual animal wastested with at least 10 days between experiments.

[0228] [II] Test Result

[0229] All of the following Test Compounds showed 100% inhibition rateof emesis in the ferret at the dose of 1.0 mg/kg.

[0230] Test compounds : The object compounds of the Examples 4-(2), 26,29, 40 and 41 (to be continued on the next page)

[0231] The following Preparations and Examples are given for the purposeof illustrating this invention.

PREPARATION 1

[0232] A mixture of 3-bromopyridine (6.25 ml), propargyl alcohol (4.9ml), bis(triphenylphosphine)palladium(II) chloride (0.45 g) and copperiodide (125 mg) in triethylamine (100 ml) was stirred under reflux for1.5 hours. After being cooled at room temperature, the reaction mixturewas filtered and the insoluble material on the filter was washed withethyl acetate (about 200 ml). The filtrate and the washing were combinedand evaporated under reduced pressure. The resulting residue waspurified bv column chromatography on silica gel using a mixed solvent ofhexane and ethyl acetate as eluent. The fractions containing theobjective compound were collected and evaporated under reduced pressureto give 3-(3-pyridyl)-2-propyn-1-ol (7.9 g) as brownish crystals.

[0233] IR (Nujol): 3160, 1480, 1460, 1400 cm⁻¹

[0234] NMR (CDCl₃, δ) 3.87 (!H, t, J=5.9Hz), 4.51 (2H, d, J=5.9Hz),7.24-7.30 (1H, m), 7.73 (1H, dd, J=1.9 and 7.4Hz), 8.52 (1H, d,J=5.1Hz), 8.78 (1H, d, J=1.9Hz)

[0235] MASS: 134 (M+H)⁺

PREPARATION 2

[0236] The following compounds were obtained according to a similarmanner to that of Preparation 1.

[0237] (1) 4-(3-Pyridyl)-3-butyn-1-ol

[0238] NMR (CDCl₃, δ): 2.61 (1H, s), 2.71 (2H, t, J=6.3Hz), 3.85 (2H, t,J=6.3Hz), 7.19-7.25 (1H, m), 7.70 (1H, dd, J=2.0, 8.0Hz), 8.48 (1H, dd,J=1.4, 5.0Hz), 8.63 (1H, d, J=1.4Hz)

[0239] MASS: 279, 148 (M+H)⁺

[0240] (2) 3-(6-Methoxypyridin-3-yl)-2-propyn-1-ol

[0241] IR (Nujol): 3300, 1610, 1560, 1490, 1490, 1370, 1350, 1310, 1300cm⁻¹

[0242] NMR (CDCl_(3, δ):) 3.94 (3H, s), 4.52 (2H, s), 6.70 (1H, dd,J=0.7, 8.6Hz), 7.60 (1H, dd, J=2.2, 8.6Hz), 8.30 (1H, d, J=2.2Hz)

[0243] MASS: 164 (M+H)⁺, 134

[0244] (3) 3-(4-Methoxypyridin-3-yl)-2-propyn-1-ol

[0245] IR (KBr): 3172, 2854, 1585, 1498 cm⁻¹

[0246] NMR (CDCl₃, δ): 3.90 (3H, s), 4.33 (2H, d, J=4.0Hz), 5.38 (1H, t,J=4.0Hz), 7.12 (1H, d, J=5.8Hz), 8.24 (2H, br s)

[0247] MASS: 164 (M+H)⁺, 134

[0248] (4) 3-[6-(tert-Butoxycarbonylamino)pyridin-3-yl]-2-propyn-1-ol

[0249] IR (Nujol): 3500, 3210, 1725, 1625, 1600, 1580, 1430, 1380 cm⁻¹

[0250] NMR (CDCl₃, δ): 1.54 (9H, s), 4.99 (2H, s), 7.70 (1H, dd, J=2.2,8.7Hz), 7.97 (1H, d, J=8.7Hz), 8.40 (1H, d, J=2.2Hz), 8.51 (1H, br s)

[0251] MASS: 217 (M+H)⁺, 175

PREPARATION 3

[0252] Thionyl chloride (11.9 g) was added dropwise to a solution of3-(3-pyridyl)-2-propyn-1-ol (13.3 g) in dichloromethane (266 ml) at roomtemperature. After completion of the addition, the mixture was stirredfor 2 hours at room temperature. The resulting precipitates werecollected by filtration and washed with diethyl ether to give1-chloro-3-(3-pyridyl)-2-propyne hydrochloride (14.5 g) as brownishcrystals.

PREPARATION 4

[0253] The following compounds were obtained according to a similarmanner to that of Preparation 3.

[0254] (1) 1-Chloro-3-(6-methoxypyridin-3-yl)-2-cropyne hydrochloride

[0255] (2) 1-Chloro-3-(4-methoxypyridin-3-yl)-2-propyne hydrochloride

PREPARATION 5

[0256] Isobutyl chloroformate (4.4 ml) was added dropwise to asuspension of (E)-3-(3-pyridyl)acrylic acid (5.0 g) andN-methylmorpholine (4.05 ml) in 1,2-dimethoxyethane (50 ml) under −18°C. After being stirred at the same temperature for 0.5 hour, a solutionof sodium borohydride (1.86 g) in water (10 ml) was added to the mixtureall at once. The resulting mixture was poured into water and extractedwith ethyl acetate. The extract was washed with brine and dried overmagnesium sulfate, and evaporated under reduced pressure. The residuewas purified by column chromatography on silica gel using a mixedsolvent of hexane and ethyl acetate as eluent. The fractions containingthe objective compound were collected and evaporated under reducedpressure to give (E)-3-(3-pyridyl)-2-propen-1-ol (1.0 g) as an oil.

[0257] NMR (CDCl₃, δ): 4.40 (2H, d, J=4.0Hz), 6.52 (1H, dt, J=4.0,16.1Hz, trans), 6.65 (1H, d, J=16.1Hz, trans), 7.45 (1H, dd, J=5.6,8.0Hz), 7.89 (1H, d, J=8.0Hz), 8.44 (1H, d, J=15.6Hz), 8.58 (1H, s)

[0258] MASS: 136 (M+H)⁺

PREPARATION 6

[0259] Methane sulfonyl chloride (0.22 ml) was added to a mixture of(E)-3-(3-pyridyl)-2-propen-1-ol (0.36 g) and triethylamine (0.74 ml) indichloromethane (5 ml) under −10° C. After being stirred at the sametemperature for 0.5 hour, the reaction mixture was washed with saturatedsodium bicarbonate, dried over magnesium sulfate and evaporated underreduced pressure to give (E)-3-(3-pyridyl)-2-propen-1-ylmethanesulfonate.

[0260] The crude mesylate was used at next step without furtherpurification.

PREPARATION 7

[0261]4-(3-Pyridyl)-3-butyn-1-yl methanesulfonate was obtained accordingto a similar manner to that of Preparation 6.

PREPARATION 8

[0262] The solution of 3-(3-pyridyl)-2-propyl-1-ol (300 mg) in methanolwas hydrogenated using Lindlar catalyst for 4 hours at atmosphericpressure. After removal of catalyst by filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel using ethyl acetate as eluent. Thefractions containing the objective compound were collected andevaporated under reduced pressure to give(Z)-3-(3-pyridyl)-2-propen-1-ol (50 mg) as an oil.

[0263] IR (Nujol): 3600-2700, 1590, 1575, 1480 cm⁻¹

[0264] NMR (CDCl₃, δ): 4.42 (2H, dd, J=1.6, 6.4Hz), 6.04 (1H, dd, J=6.4,12.0Hz, cis), 6.52 (1H, d, J=12.0Hz, cis), 7.25-7.31 (1H, m), 7.55 (1H,d, J=8.0Hz), 8.30-8.70 (2H, br s)

[0265] MASS: 136 (M+H)⁺

PREPARATION 9

[0266] A mixture of 4-formyl-1-methylimidazole (3.0 g) andtriethylphosphonoacetate (6.3 g) in N,N-dimethylformamide (30 ml) wasstirred under ice-cooling. After several minutes, sodium hydride (1.63g, 60% in mineral oil) was added to the mixture, which was stirred for30 minutes at the same temperature. The resulting mixture was pouredinto ice-water, neutralized with aqueous ammonium acetate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and concentrated under reduced pressure togive ethyl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate (4.63 g).

[0267] IR (Nujol): 2900, 1700, 1625 cm⁻¹

[0268] NMR (CDCl₃, δ): 1.31 (3H, t, J=7.1Hz), 3.70 (3H, s), 4.23 (2H, q,J=7.1Hz), 6.53 (1H, d, J=15.6Hz), 7.07 (1H, s), 7.45 (1H, s), 7.54 (1H,d, J=15.6Hz) MASS: 181 (M+H)⁺

PREPARATION 10

[0269] A solution of ethyl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate(2.5 g) in tetrahydrofuran (100 ml) was hydrogenated over 10% palladiumactivated carbon (0.2 g) at room temperature under 2 atmosphericpressure. After removal of catalyst by filtration through Celite pad,the filtrate was concentrated under reduced pressure to give ethyl3-(1-methyl-1H-imidazol-4-yl)propionate (2.63 g).

[0270] IR (Neat): 2900, 1720 cm⁻¹

[0271] NMR (CDCl₃, δ): 1.24 (3H, t, J=7.1Hz), 2.62 (2H, t, J=7.4Hz),2.89 (2H, t, J=7.4Hz), 3.62 (3H, s), 4.16 (2H, q, J=7.1Hz), 6.64 (1H,s), 7.33 (1H, s)

[0272] MASS: 183 (M+H)⁺

PREPARATION 11

[0273] To an ice-cooled solution of ethyl3-(1-methyl-1H-imidazol-4-yl)propionate (2.63 g) in tetrahydrofuran (26ml) was added lithium aluminum hydride (0.55 g) by small portions undernitrogen atmosphere. After the mixture was stirred for 0.5 hour, waterand 15% aqueous sodium hydroxide solution were added successively to themixture. The resulting precipitates were filtrated off through Celitepad and the filtrate was extracted with ethyl acetate. The organic layerwas washed with water and brine successively, dried over magnesiumsulfate and concentrated under reduced pressure. The resulting residuewas purified by column chromatography on silica gel usingdichloromethane-methanol (100:1) as eluent to give3-(1-methyl-1H-imidazol-4-yl)-1-propanol (940 mg).

[0274] IR (Neat): 3250, 2900 cm ⁻¹

[0275] NMR (CDCl₃, δ): 1.86 (2H, m), 2.69 (2H, t, J=6.7Hz), 3.63 (3H,s), 3.73 (2H, t, J=6.0Hz), 6.62 (1H, s), 7.34 (1H, s)

[0276] MASS: 141 (M+H)⁺

PREPARATION 12

[0277] To a solution of oxalyl chloride (0.361 ml) in dichloromethane(10 ml) cooled below −65° C. with a dry ice-acetone bath, a solution ordimethyl sulfoxide (0.381 ml) in dichloromethane (1 ml) was added withefficient stirring over 10 minutes. After 20 minutes below −65° C., asolution of 3-(1-methyl-1H-imidazol-4-yl)-1-propanol in dichloromethane(2 ml) was added to the mixture over 10 minutes below −65° C. and themixture was stirred at the same temperature for 20 minutes and then at−45° C. ˜−40° C. for 30 minutes. After addition of triethylamine (1.0ml) dropwise to the mixture over 1 minute followed by stirring for 30minutes, the reaction mixture was concentrated in vacuo. The resultingresidue was purified by column chromatography on silica gel usingdichloromethane-methanol (20:1) as eluent to give3-(1-methyl-1H-imidazol-4-yl)propanol (103 mg).

[0278] IR (Neat): 1715 cm⁻¹

[0279] NMR (CDCl₃, δ): 2.85 (4H, m), 3.63 (3H, s),, 6.63 (1H, s), 7.34(1H, s), 9.83 (1H, s)

[0280] MASS: 139 (M+H)⁺

PREPARATION 13

[0281] The following compound was obtained according to a similar mannerto that of Preparation 12.

[0282] 4-Formyl-1-(triphenylmethyl)pyrazole

[0283] NMR (DMSO-d₆, δ): 7.05-7.10 (6H, m), 7.36-7.41 (9H, m), 8.15 (2H,s), 9.81 (!H, s)

PREPARATION 14

[0284] To a solution of (3R)-4-benzyl-3-(hydroxymethyl)-morpholine(13.67 g) in methanol (140 ml) and water (10 ml) was added ammoniumformate (10.4 g) and palladium on activated carbon (50%, 1.4 g). Theresulting mixture was stirred at 60° C. for 3 hours. After removal ofinsoluble material by filtration, the filtrate was concentrated underreduced pressure to give crude amine (16.43 g). To a solution of theobtained amine in tetrahydrofuran (160 ml) were added triethylamine(32.2 ml) and di-tert-butyl dicarbonate (50.4 g) at 0°. After stirringat room temperature for 12 hours, the mixture was quenched with waterand extracted with ethyl acetate three times. The organic layer waswashed with brine, dried over magnesium sulfate, and evaporated underreduced pressure to give crude oil which was purified by columnchromatography on a silica gel using a mixture of ethyl acetate andhexane (6:4) as eluent to give-(3R)-4-(tert-butoxycarbonyl)-3-(hydroxymethyl)morpholine (8.64 g) as acolorless solid.

[0285] NMR (CDCl₃, δ): 1.47 (9H, s), 3.16-3.24 (1H, m), 3.40-3.61 (2H,m), 3.71-4.00 (6H, m)

PREPARATION 15

[0286] The following compound was obtained according to a similar mannerto that of Preparation 14.

[0287] (2R,2S)-4-(tert-Butoxycarbonyl)-2-(hydroxymethyl)-morpholine

[0288] IR (Neat): 1695 cm⁻¹

[0289] NMR (CDCl₃, δ): 1.47 (9H, m), 2.03 (1H, t, J=6.7Hz), 2.70-3.00(2H, m), 3.45-3.74 (4H, m), 3.84-3.95 (3H, m)

PREPARATION 16

[0290] The following compounds were obtained according to a similarmanner to that of Preparation 12.

[0291] (1) (3S)-4-(tert-Butoxycarbonyl)-3-formylmorpholine

[0292] IR (KBr): 1734, 1695 cm⁻¹

[0293] NMR (CDCl₃, δ): 1.47 (9H, s), 3.00-3.30 (1H, m), 3.48 (1H, dt,J=2.8, 11.7Hz), 3.67 (1H, dt, J34.2, 12.1Hz), 3.60-3.90 (2H, m),4.25-4.50 (2H, m), 9.66 (1H, s)

[0294] (2) (2R,2S)-4-(tert-Butoxycarbonyl)-2-formylmorpholine

[0295] IR (Neat): 1737, 1681 cm ⁻¹

[0296] NMR (CDCl₃, δ): 1.47 (9H, m), 2.80-5.00 (7H, m), 9.65 (1H, m)

PREPARATION 17

[0297] The following compounds were obtained according to a similarmanner to that of Preparation 9.

[0298] (1) Ethyl (2E)-3-[(3R)-4-(tert-butoxycarbonyl)morpholin-3-yl]acrylate

[0299] IR (Neat): 2978, 1716, 1697 cm⁻¹

[0300] NMR (CDCl₃, δ): 1.26 (3H, t, J=7.4Hz), 1.46 (9H, s), 3.16 (1H,dt, J=3.7, 13.2Hz), 3.49 (1H, dt, J=2.9, 11.9Hz), 3.69 (1H, dd, J=3.6,11.7Hz), 3.80-3.99 (3H, m), 4.21 (2H, q, J=7.1Hz), 4.50-4.60 (1H, m),5.93 (1H, dd, J=1.8, 15.9Hz), 6.99 (1H, dd, J=5.3, 15.9Hz)

[0301] (2) Ethyl(2E)-3-[(2R,2S)-(4-tert-butoxycarbonyl)morpholin-2-yl]acrylate

[0302] IR (Neat): 1737, 1681 cm⁻¹

[0303] NMR (CDCl₃, δ): 1.27 (3H, t, J=3.3Hz), 1.47 (9H, s), 2.30-3.10(3H, m), 3.57 (1H, dt, J=2.7, 11.3Hz), 3.80-4.20 (3H, m), 4.21 (2H, q,J=-7.1Hz), 6.12 (1H, dd, J=1.7, 15.8Hz), 6.83 (1H, dd, J=4.2, 15.8Hz)

PREPARATION 18

[0304] To a solution of ethyl(2E)-3-[(3R)-4-(tert-butoxycarbonyl)morpholin-3-yl]acrylate (1.0 g) intoluene (10 ml) was added dilsobutylaluminum hydride (1.02 M in toluene,7.6 ml) at −78° C. ˜−40° C. After stirring for 2 hours at 0° C., themixture was quenched with methanol (1.2 ml), and stirred for 1 hour atroom temperature. After the resulting precipitate was filtered off, thefiltrate was evaporated and purified by column chromatography on asilica gel using a mixture of ethyl acetate and hexane (3:7˜4:6) aseluent to give(3R)-4-(tert-butoxycarbonyl)-3-[(E)-3-hydroxy-1-propenyl]morpholine(0.71 g) as a colorless oil.

[0305] IR (Neat): 1691 cm⁻¹

[0306] NMR (CDCl₃, δ): 1.47 (9H, s), 3.17 (1H, dt, J=3.7, 12.2Hz), 3.48(1H, dt, J=2.7, 11.3Hz), 3.65 (1H, dd, J=3.4, 11.6Hz), 3.70-3.91 (3H,m), 4.17-4.19 (2H, m), 4.40-4.50 (1H, m), 5.82-5.93 (2H, m)

PREPARATION 19

[0307] The following compound was obtained according to a similar mannerto that of Preparation 18.

[0308](2R,2S)-4-(tert-Butoxycarbonyl)-2-[(E)-3-hydroxy-1-propenyl]morpholine

[0309] NMR (CDCl₃, δ): 1.47 (9H, s), 2.62-3.00 (2H, m), 3.56 (1H, dt,J=2.7, 11.4Hz), 3.81-3.94 (4H, m), 4.18 (2H, d, J=5.0Hz), 5.64-6.04 (2H,m)

PREPARATION 20

[0310] The following compounds were obtained according to a similarmanner to that of Preparation 6.

[0311] (1)(3R)-4-(tert-Butoxycarbonyl)-3-[(E)-3-methanesulfonyl-oxy-1-propenyl]morpholine

[0312] NMR (CDCl₃, 67 ): 1.47 (9H, s), 3.02 (3H, s), 3.10-3.25 (1H, m),3.48 (1H, dt, J=2.8, 11.5Hz), 3.63-3.93 (4H, m), 4.45-4.55 (1H, m), 4.74(2H, d, J=6.2Hz), 5.75-5.86 (1H, m), 6.05 (1H, dd, J=5.5, 15.6Hz)

[0313] (2)(2R,2S)-4-(tert-Butoxycarbonyl)-2-[(E)-3-methanesulfonyloxy-1-propenyl]morpholine

[0314] NMR (CDCl₃, δ): 1.47 (9H, m), 2.60-2.72 (1H, m), 2.89-3.02 (1H,m), 3.02 (3H, s), 3.55 (1H, dt, J=2.7, 11.4Hz), 3.82-4.00 (4H, 4), 4.73(2H, d, J=5.1Hz), 5.79-6.01 (2H, m)

PREPARATION 21

[0315] To a mixture of 1-amino-1-cyclopropanemethanol hydrochloride (1.1g), benzaldehyde (945 mg) and triethylamine (1.24 ml) in1,2-dichloroethane (10 ml), sodium triacetoxyborchydride (5.66 g) wasadded with ice-cooling over 5 minutes. After being stirred at roomtemperature for 13 hours, the mixture was poured into aqueous sodiumbicarbonate solution and stirred for several hours. The organic layerwas separated, dried over magnesium sulfate and evaporated under reducedpressure to give 1-(N-benzylamino)-1-cyclopropanemethanol (641 mg).

[0316] IR (Nujol): 3300-2700 cm⁻¹

[0317] NMR (CDCl₃, δ): 0.50-0.77 (4H, m), 3.51 (2H, s), 3.84 (2H, s),7.19-7.36 (5H, s)

[0318] MASS: 178 (M+H)⁺

PREPARATION 22

[0319] The following compound was obtained according to a similar mannerto that of Preparation 19.

[0320] (2S)-2-(N-Benzylamino)-4-methyl-1-pentanol

[0321] NMR (CDCl₃, δ): 0.84-0.94 (6H, m), 1.17-1.70 (3H, m), 2.72-2.81(1H, m), 3.28 (1H, dd, J=6.0, 10.6Hz), 3.66 (1H, dd, J=3.9, 10.6Hz),3.78 (2H, s), 7.20-7.38 (5H, m)

[0322] MASS: 208 (M+H)⁺

PREPARATION 23

[0323] Chloroacetyl chloride (421 mg) was added dropwise to a mixture of1-(N-benzylamino)-1-cyclopropanemethanol (600 mg) and powdered potassiumcarbonate (702 mg) in dichloromethane (6 ml) with ice-cooling and thenthe mixture was stirred at room temperature for 2 hours. The resultingmixture was washed with diluted hydrochloric acid and brinesuccessively, and concentrated under reduced pressure. A mixture of theoil obtained by the above procedure and potassium tert-butoxide (380 mg)in tert-butanol (6 ml) was stirred for 2 hours under reflux. After beingcooled to room temperature, the mixture was diluted with ethyl acetate(10 ml). The resulting mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was dissolved withethyl acetate and the ethyl acetate solution was washed with dilutedhydrochloric acid and brine successively, dried over magnesium sulfateand concentrated under reduced pressure to give a solid of4-benzyl-5-oxo-7-oxa-4-azaspiro[2.5]octane (695.3 mg).

[0324] IR (KBr): 3100-2800, 1643 cm⁻¹

[0325] NMR (DMSO-d₆, δ): 0.64-1.02 (4H, m), 3.69 (2H, s), 4.43 (2H, s),4.45 (2H, s), 7.17-7.37 (2H, m)

[0326] MASS: 218 (M+H)⁺

PREPARATION 24

[0327] The following compound was obtained according to a similar mannerto that of Preparation 21.

[0328] (5S)-4-Benzyl-5-(2-methylpropyl)-3-morpholinone

[0329] IR (Neat): 1655 cm⁻¹

[0330] NMR (CDCl₃, δ): 0.83 (3H, d, J=6.3Hz), 0.95 (3H, d, J=6.4Hz),1.33-1.60 (2H, m), 1.79-1.92 (1H, m), 3.08-3.17 (1H, m), 3.56-3.79 (1H,m), 3.82 (2H, d, J=15.0Hz), 4.23 and 4.27 (2H, ABq, J=16.7Hz), 5.47 (1H,d, J=14.9Hz), 7.24-7.39 (5H, m)

[0331] MASS: 248 (M+H)⁺

PREPARATION 25

[0332] A solution of 4-benzyl-5-oxo-7-oxa-4-azaspiro[2.5]octane (695.3mg) in tetrahydrofuran (8 ml) was added dropwise to an ice-cooledsuspension of lithium aluminum hydride (112 mg) in tetrahydrofuran (5ml) over 20 minutes and then the mixture was stirred at 50° C. for 2hours under nitrogen atmosphere. After being cooled to room temperature,sodium fluoride (495 mg) was added to the mixture. The mixture wasstirred vigorously and cooled with ice-bath. Water (0.16 ml) was addedthereto and the mixture was filtered. The filtrate was concentratedunder reduced pressure to give an oil. The oil was purified by columnchromatography on silica gel using a mixture of hexane and ethyl acetateas eluent to give 4-benzyl-7-oxa-4-azaspiro[2.5]octane (334.8 mg).4-Benzyl-7-oxa-4-azaspiro[2.5]octane in ethanol (8 ml) was hydrogenatedover palladium hydroxide on carbon for 2 hours at atmospheric pressure.After removal of the catalyst by filtration, the filtrate was treatedwith 4N hydrogen chloride in ethyl acetate (2 ml) and concentrated underreduced pressure to give 7-oxa-4-azaspiro[2.5]octane hydrochloride (81mg).

[0333] IR (KBr): 3350, 3000-2400 cm⁻¹

[0334] NMR (CDCl₃, δ): 0.84-1.10 (4H, m), 3.75 (2H, s), 3.90-4.10 (4H,m), 10.11 (1H, br s)

[0335] MASS: 114 (M+H)⁺ (free)

PREPARATION 26

[0336] The following compound was obtained according to a similar mannerto that of Preparation 23.

[0337] (3S)-4-Benzyl-3-(2-methylpropyl)moroholine

[0338] NMR (CDCl₃, δ): 0.89 (3H, d, J=6.2Hz), 0.93 (3H, d, J=6.3Hz),1.20-1.40 (1H, m), 1.46-1.61 (2H, m), 2.17-2.27 (1H, m), 2.40-2.50 (1H,m), 2.59-2.68 (1H, m), 3.16 (1H, d, J=13.3Hz), 3.40 (1H, dd, J=11.2,7.8Hz), 3.59-3.83 (3H, m), 4.04 (1H, d, J=13.3Hz), 7.21-7.36 (5H, m)

[0339] MASS: 234 (M+H)⁺

PREPARATION 27

[0340] The following compound was obtained according to a similar mannerto that of Preparation 23.

[0341] (3S)-3-(2-Methylpropyl)morpholine hydrochloride

[0342] NMR (DMSO-d₆, δ): 0.87 (3H, s), 0.90 (3H, s), 1.26-1.52 (2H, m),1.65-1.78 (1H, m), 3.12-3.48 (4H, m), 3.69 (1H, dt, J=3.4, 12.3Hz),3.87-3.95 (2H, m)

[0343] MASS: 144 (M+H)⁺ (free)

PREPARATION 28

[0344] A solution of 2-amino-5-bromopyridine (5.0 g) and di-tert-butyldicarbonate (6.39 g) in tert-butanol (100 ml) was stirred at roomtemperature for 15 hours. The resulting suspension was concentratedunder reduced pressure and the residue was chromatographed on a silicagel using dichloromethane eluent. The fractions containing the objectivecompound were collected and concentrated under reduced pressure to give2-(tert-butoxycarbonylamino)-5-bromopyridine (3.25 g).

[0345] IR (Nujol): 3210, 1720, 1580, 1525, 1460, 1370 cm⁻¹

[0346] NMR (CDCl₃, δ): 1.56 (9H, 5), 7.76 (1H, dd, J=2.5, 8.9Hz), 7.95(1H, d, J=8.9Hz), 8.38 (1H, d, J=2.5Hz), 8.93 (1H, br s)

PREPARATION 29

[0347] To a solution of(2R)-4-benzyl-1-(3,5-dichlorobenzoyl)-2-(3,4-damethylbenzyl)piperazine(5.03 g) in dichloromethane (50 ml) was added 1-chloroethylchloroformate (1.51 ml) slowly at 0° C., and then the mixLure was heatedat reflux under stirring. After 5.5 hours, the solvent was removed invacuo and then the resulting residue was dissolved in methanol (20 ml)and refluxed for 0.5 hour. After removal of the solvent, the resultingresicue was triturated with isopropyl ether to afford(2R)-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)piperazinehydrochloride (4.84 g).

[0348] IR (Nujol): 3350, 1625 cm⁻¹

[0349] NMR (DMSO-d₆, δ): 2.10-4.60 (15Hz m), 6.50-9.70 (6H, m)

[0350] MASS: 377 (M+H)⁺ (free)

PREPARATION 30

[0351] The following compounds were obtained according to a similarmanner to that of Preparation 29.

[0352] (1)(2R)-1-(3,5-Dichlorobenzoyl)-2-[(1H-indol-3-yl)methyl]-piperazinehydrochloride

[0353] IR (KBr): 1637 cm⁻¹

[0354] NMR (DMSO-d₆, δ): 2.80-4.80 (9H, m), 6.80-10.20 (8H, m)

[0355] MASS: 388 (M+H)⁺ (free)

[0356] (2) (2R)-1-(3,5-Dichlorobenzoyl)-2-(2-naphthylmethyl)-piperazinehydrochloride

[0357] NMR (DMSO-d₆, δ): 2.80-4.70 (9H, m), 6.50-8.00 (10H, m)

[0358] MASS: 399 (M+H)⁺ (free)

[0359] (3)(2R)-1-(3,5-Dichlorobenzoyl)-2-[4-(trifluoromethyl)-benzyl]piperazinedihydrochloride

[0360] IR (KBr): 3430, 2930, 2790, 1648, 1164 cm⁻¹

[0361] NMR (DMSO-d₆, δ): 2.70-5.30 (9H, m), 6.50-7.90 (7H, m), 9.62 (1H,br s)

[0362] MASS: 417 (M+H)⁺ (free)

[0363] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)piperazinehydrochloride

[0364] IR (KBr): 3700-3200, 1639, 1281, 1136 cm⁻¹

[0365] NMR (DMSO-d₆, δ): 2.90-3.80 (7H, m), 4.40-5.30 (2H, m), 6.90-8.30(10H, m)

[0366] MASS: 317 (M+H)⁺ (free)

PREPARATION 31

[0367](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)piperazinefumarate (2 g) was treated with 10% aqueous sodium hydroxide solution(14 ml) and dichloromethane (14 ml). The organic layer was separated,washed with brine, dried over magnesium sulfate and evaporated underreduced pressure. A mixture of free piperazine derivative obtained bvthe above procedure, potassium carbonate (0.76 g) and1,4-dichloro-2-butyne (0.43 ml) in N,N-dimethylformamide (15 ml) wasstirred for 4.5 hours at room temperature. The reaction mixture waspoured into water (75 ml) and extracted with ethyl acetate. The extractwas washed with brine, dried over magnesium sulfate and evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel using a mixed solvent of toluene and ethyl acetate (10:1) aseluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-chloro-2-butynyl)-2-(2-naphthylmethyl)piperazine(1.18 g).

[0368] IR (Neat): 3600-3100, 1638, 1275, 1127, 900 cm⁻¹

[0369] NMR (CDCl₃, δ): 2.31-5.30 (13H, m), 6.90-7.95 (10H, m)

[0370] MASS: 553 (M+H)⁺

EXAMPLE 1

[0371] (1) A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]piperazine(0.67 g), 1-chloro-3-(3-pyridyl)-2-propyne nydrochloride (0.3 g) andpotassium carbonate (0.52 g) in N,N-dimethylformamide (5 ml) was stirredfor 5 hours at 50° C. The mixture was poured into water and extractedwith ethyl acetate. The extract was washed with brine, dried overmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel using ethyl acetate aseluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[3-(3-pyridyl)-2-propynyl]-piperazine(0.25 g) as a syrup.

[0372] (2) The following compound was prepared by treatment of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)-methyl]-4-[3-(3-pyridyl)-2-propynyl]piperazinewith 4N hydrochloric acid in ethyl acetate.

[0373](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[1H-indol-3-yl-)methyl]-4-[3-1,3-pyridyl)-2-propynyl]piperazinedihydrochloride

[0374] mp: 180-190° C.

[0375] [α]_(D) ^(24.6): −10.50° (C=0.1, MeOH)

[0376] IR (Nujol): 3600-3200, 2700-2500, 1643, 1530, 1428, 1361, 1280cm⁻¹

[0377] NMR (DMSO-d₆, δ): 3.20-5.20 (1H, m), 6.40-8.30 (10H, m),8.74-8.80 (1H, m), 8,85-8.90 (2H, m), 10.90-11.10 (1H, m)

[0378] MASS: 571 (M+H)⁺ (free)

[0379] Elemental Analysis Calcd. for C₃₀H₂₄F₆N₄O.2HCl.1.8H₂O: C 53.31, H4.41, N 8.29 Found: C 53.28, H 4.53! N 7.87

EXAMPLE 2

[0380] The following compounds were obtained according to a sirmilarmanner to that of Example 1.

[0381] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(6-methoxypyridin-3-yl)-2-propynyl]piperazinedihydrochloride

[0382] mp: 160-170° C.

[0383] [α]_(D) ^(24.2): −14.72° (C=0.55, MeOH)

[0384] IR (KBr):3600-3300, 2700-2500, 1648, 1617, 1494, 1430, 1280 cm⁻¹

[0385] NMR (DMSO-d₆, δ): 2.05-2.20 (6H, m), 2.80-5.20 (11H, m), 3.90(3H, s), 6.50-8.40 (9H, m)

[0386] MASS: 590 (M+H)⁺ (free)

[0387] Elemental Analysis Calcd. for C₃₁H₂₉F₆N₃O₂.2HCl.0.5H₂O: C 55.45,H 4.80, N 6.26 Found: C 55.28, H 4.86, N 6.12

[0388] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[3-(6-methoxypyridin-3-yl)-2-propynyl]-piperazinedihydrochloride

[0389] mp: 183-189° C.

[0390] [α]_(D) ^(23.9): −21.0° (C=0.55, MeOH)

[0391] IR (KBr): 3600-3300, 2700-2500, 1644, 1602, 1494, 1428, 1280 cm⁻¹

[0392] NMR (DMSO-d₆, δ): 3.20-5.20 (11H, m), 3.90 (3H, s), 6.60-8.40(11H, m), 10.95 (1H, br s), 12.00-12.40 (2H, m)

[0393] MASS: 600 (M+H)⁺ (free)

[0394] Elemental Analysis Calcd. for C₃₁H₂₆F₆N₄O₂.2HCl.H₂O: C 53.85, H4.37, N 8.10 Found: C 53.90, H 4.36, N 8.02

[0395] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[3-(2-pyridyl)-2-propynyl]piperazine

EXAMPLE 3

[0396](2R)-1-[3,-5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(2-pyridyl)-2-propynyl]piperazinedihydrochioride (0.2 g) was made free with saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate. The extract wasdried over magnesium sulfate and evaporated under reduced pressure. Theresulting residue dissolved in methanol (10 ml) and the solution washydrogenated over 10% palladium on activated carbon (50 mg) at roomtemperature under 2-3 atoms. After removal of catalyst by filtration,the filtrate was concentrated under reduced pressure. The residue wastreated with 4N hydrogen chloride in ethyl acetate solution to give(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(2-pyridyl)propyl]-piperazinedihydrochloride.

[0397] mp: 120-130° C.

[0398] [α]_(D) ^(24.5): −12.81° (C=0.32, MeOH)

[0399] IR (Nujol): 3600-3300, 2700-2500, 1635, 1450, 1380, 1280 cm⁻¹

[0400] NMR (DMSO-d₆, δ): 2.00-5.20 (21H, m), 6.60-7.80 (5H, m), 7.80(1H, d, J=8.0Hz), 7.88 (1H, t, J=-7.0Hz), 8.18 (1H, s), 8.49 (1H, t,J=7.1Hz), 8.81 (1H, d, J=5.2Hz), 11.20-12.20 (2H, m)

[0401] MASS: 564 (M+H)⁺ (free)

[0402] Elemental Analysis Calcd. for C₃₀H₃₁F₆N₃O.2HCl.2.7H₂O: C 52.59, H5.65, N 6.13 Found: C 52.66, H 5.78, N 5.77

EXAMPLE 4

[0403] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[3-(3-pyridyl)propyl]piperazinedihydrochioride

[0404] mp: 150-160° C.

[0405] [α]_(D) ^(22.9): −2.86° (C=0.42, MeOH)

[0406] IR (KBr): 3600-3000, 2700-2010, 1641, 1554, 1461, 1428, 1280 cm⁻¹

[0407] NMR (DMSO-d₆, δ): 2.10-5.20 (15H, m), 6.60-8.30 (9H, m),8.45-8.55 (1H, m), 8.80-9.00 (2H, m), 10.95-11.05 (1H, m), 11.90-12.00(2H, br s)

[0408] MASS: 575 (M+H)⁺ (free)

[0409] Elemental Analysis Calcd. for C₃₀H₂₈F₆N₄O.2HCl.1.2H₂O: C 50.71, H5.25, N 7.89 Found: C 50.65, H 5.35, N 7.20

[0410] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[3-(2-pyridyl)propyl]piperazinedihydrochloride

[0411] mp: 80-100° C.

[0412] [α]_(D) ^(23.1): −5.29° (C=0.86, MeOH)

[0413] IR (KBr): 3600-3300, 2700-2500, 1637, 1617, 1400, 1282 cm⁻¹

[0414] NMR (DMSO-d_(61 δ):) 2.20-2.40 (2H, m), 3.10-5.20 (13H, m),6.60-8.30 (10H, m), 8.49 (1H, d, J=7.8Hz), 8.80 (1H, d, J=5.0Hz),10.90-11.05 (1H, br s)

[0415] MASS: 575 (M+H)⁺ (free)

[0416] Elemental Analysis Calcd. for C₃₀H₂₈F₆N₄O.2HCl.1.2H₂O: C 53.85, H4.88, N 8.37 Found: C 53.92, H 5.30, N 7.66

[0417] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[4-(3-pyridyl)butyl]piperazinedihydrochloride

[0418] mp: 140-145° C.

[0419] [α]_(D) ^(22.3): −8.33° (C=0.30, MeOH)

[0420] IR (Nujol): 3600-3000, 2700-2300, 1641, 1465, 1430, 1280 cm⁻¹

[0421] NMR (DMSO-d₆, δ): 1.60-5.20 (17H, m), 6.60-9.00 (12H, m), 11.00(1H, br s), 11.59 (2H, br s)

[0422] MASS: 589 (M+H)⁺ (free)

[0423] Elemental Analysis Calcd. for C₃₁H₃₀F₆N₄O.2HCl.2H₂O: C 53.38, H5.20, N 8.03 Found: C 53.47, H 5.28, N 7.51

EXAMPLE 5

[0424] (1) Methanesulfonyl chloride (0.094 ml) was added to a mixture of(Z)-3-(3-pyridyl)-2-propen-1-ol (0.15 g) and triethylamine (0.2 ml) indichloromethane (2 ml) under −10° C. After being stirred at the sametemperature for 0.5 hour, the reaction mixture was washed with saturatedsodium bicarbonate, dried over magnesium sulfate and evaporated underreduced pressure. The obtained mesylate was added to a mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]piperazine(0.5 g), powdered potassium carbonate (0.61 g) and catalytic amount ofpotassium iodide in a mixed solvent of acetonitrile (10 ml) andN,N-dimethylformamide (2 ml). The resulting mixture was stirred at 50°C. for 1.5 hours and then filtered. The filtrate was evaporated underreduced pressure and the resulting residue was purified by columnchromatography on silica gel using a mixed solvent of dichloromethaneand methanol as eluent. The fractions containing the objective compoundwere collected and evaporated under reduced pressure to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[(Z)-3-(3-pyridyl)-2-propenyl]piperazine(0.49 g) as a syrup.

[0425] NMR (CDCl₃, δ): 1.80-5.20 (11H, m), 5.97 (H, dt, J=6.6, 11.7Hz,cis), 6.60 (1H, d, J=11.7Hz, cis), 6.80-8.00 (10H, m), 8.23 (1H, s),8.45-8.60 (2H, m)

[0426] MASS: 562 (M+H)⁺

[0427] (2) The following compound was prepared bv treatment of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[1H-indol-3-yl)-methyl]-4-[(Z)-3-(3-pyridyl)-3-propenyl]piperazinewith 4N hydrogen chloride in ethyl acetate.

[0428](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[(Z)-3-(3-pyridyl)-2-propenyl]piperazinedihydrochloride

[0429] mp: 165-177° C.

[0430] [α]_(D) ^(22.9): +14.9° (C=0.50, MeOH)

[0431] IR (KBr): 3600-3300, 2700-2500, 1641, 1457, 1427, 1359, 1280,1184 cm⁻¹

[0432] NMR (DMSO-d₆, δ): 3.00-5.20 (11H, m), 6.40-8.40 (12H, m),8.70-8.85 (2H, m), 11.05 (1H, br s), 12.00 (2H, m)

[0433] MASS: 573 (M+H)⁺ (free)

[0434] Elemental Analysis Calcd. for C₃₀H₂₆F₆N₄O.2HCl.2.5H₂O: C 52.18, H4.82, N 8.11 Found: C 52.34, H 4.73, N 8.01

EXAMPLE 6

[0435] The following compounds were obtained according to a similarmanner to that of Example 5.

[0436] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-3-(3-pyridyl)-2-propenyl]-piperazinedihydrochloride

[0437] mp: 170-174° C.

[0438] [α]_(D) ^(24.1): −8.50° (C=0.20, MeOH)

[0439] IR (KBr): 3600-3300, 2700-2500, 1643, 1554, 1432, 1367, 1280 cm⁻¹

[0440] NMR (DMSO-d₆, δ): 2.00-2.30 (6H, m), 2.80-5.20 (6H, m), 6.60-9.05(12H, m)

[0441] MASS: 562 (M+H)⁺ (free)

[0442] Elemental Analysis Calcd. for C₃₀H₂₉F₆N₃O.2HCl.2.0H₂O: C 53.74, H5.26, N 6.27 Found: C 53.71, H 5.33, N 5.83

[0443] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl-)methyl]-4-[4-(3-pyridyl)-3-butynyl]piperazine

[0444] NMR (CDCl₃, δ): 2.20-5.20 (13H, m), 6.80-8.00 (10H, m), 8.15 (1H,s), 8.49 (1H, d, J=3.8Hz), 8.64 (1H, br s)

[0445] MASS: 585 (M+H)⁺

[0446] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(1H-pyrazol-1-yl)propyl]piperazinehydrochloride

[0447] mp: 73-75° C.

[0448] [α]_(D) ^(24.7): −17.300 (C=0.50, MeOH)

[0449] IR (KBr): 1640 cm⁻¹

[0450] NMR (DMSO-d₆, δ): 1.85-5.20 (21H, m), 6.20-8.30 (9H, m)

[0451] MASS: 553 (M+H)⁺ (free)

[0452] Elemental Analysis Calcd. for C₂₈H₃₁ClF₆N₄O.2H₂O: C 53.80, H5.64, N 8.96 Found: C 53.67, H 5.56, N 7.83

EXAMPLE 7

[0453] The following compounds were obtained according to a similarmanner to that of Example 5-(2). (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[3-(2-pyridyl)-2-propynyl]piperazine dihydrochloride

[0454] mp: 160-166° C.

[0455] [α]_(D) ^(24.7): −16.80° (C=0.50, MeOH)

[0456] IR (KBr): 3600-3200, 2700-2500, 1643, 1540, 1380, 1280 cm⁻¹

[0457] NMR (DMSO-d₆, δ): 3.20-5.20 (11H, m), 6.60-8.30 (11H, m), 8.65(1, d, J=2.7Hz), 10.90-11.05 (1H, m)

[0458] MASS: 571 (M+H)⁺ (Free), 607

[0459] Elemental Analysis Calcd. for C₃₀H₂ F₆N₄O.2HCl.1.5H₂O: C 53.74, H4.36, N 8.36 Found : C 53.73, H 4.66, N 7.71

[0460] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(!H-indol-3-yl)methyl]-4-[4-(3-pyridyl)-3-butynyl]piperazinedihydrochloride

[0461] mp: 175-185° C.

[0462] [α]_(D) ^(21.7): −10.30° (C=0.50, MeOH)

[0463] IR (KBr): 3600-3300, 2700-2500, 1641, 1459, 1428, 1368, 1282 cm⁻¹

[0464] NMR (DMSO-d₆, δ): 3.20-5.20 (13H, m), 6.60-8.30 (9H, m),8.65-8.85 (2H, m), 10.99 (1H, s), 11.90-12.10 (2H, m)

[0465] MASS: 585 (M+H)⁺ (free)

[0466] Elemental Analysis Calcd. for C₃₁H₂₆F₆N₄O.2HCl.1.2H₂O: C 54.83, H4.51, N 8.25 Found: C 54.79, H 4.87, N 7.67

EXAMPLE 8

[0467] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-(4-chloro-2-butynyl)piperazine(0.25 g), (R)-2-(methoxymethyl)pyrrolidine (0.10 g), potassium carbonate(0.25 g) and potassium iodide (10 mg) in dry N,N-dimethylformamide (5ml) was stirred for 5 hours at room temperature. The mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withbrine, dried over magnesium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel using ethyl acetate as eluent and treated with 4N hydrogen chloridein ethyl acetate solution to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[4-[(2R)-2-(methoxymethyl)-pyrrolidino]-2-butynyl]piperazinedihydrochloride (0.19 g).

[0468] mp: 190-195° C.

[0469] [α]_(D) ^(24.8): +9.3° (C=0.50, MeOH)

[0470] IR (Nujol): 3600-3300, 2700-2500, 1641, 1552, 1428, 1280 cm⁻¹

[0471] NMR (DMSO-d₆, δ): 1.6-2.40 (4H, m), 3.10-5.20 (18H, m), 6.60-8.30(8H, m), 11.50-11.70 (3H, m)

[0472] MASS: 621 (M+H)⁺ (free)

[0473] Elemental Analysis Calcd. for C₃₂H₃₄F₆N₄O₂.2HCl.1.5H₂O: C 53.34,H 5.46, N 7.78 Found: C 53.35, H 5.54, N 7.60

EXAMPLE 9

[0474] To a mixture of 3,5-dichlorobenzoic acid (2.6 g),(3R)-1-benzyl-3-(3,4-dimethylbenzyl)piperazine dihydrochloride (5.0 g)and triethylamine (8.54 ml) in dichloromethane (80 ml) was added2-chloro-1-methylpyridinium iodide (3.83 g) under ice-cooling, and thenthe mixture was stirred at room temperature for 1 hour. The mixture wasevaporated under reduced pressure, and the resulting residue wasdissolved into ethyl acetate. The ethyl acetate solution was filtratedand evaporated under reduced pressure. The resulting residue wasnurified by column chromatoaraphy on silica gel using hexane-ethylacetate (10:1) as eluent to give(2R)-4-benzyl-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)piperazine(5.58 g)

[0475] IR (Nujol): 2500, 1635 cm⁻¹

[0476] NMR (DMSO-d₆, δ): 1.90-2.30 (8H, m), 2.55-4.80 (9H, m), 6.50-7.15(5H, m), 7.20-7.40 (5H, m), 7.59 (1H, br)

[0477] MASS: 467 (M+H)⁺

EXAMPLE 10

[0478] The following compound was obtained according to a similar mannerto that of Example 9.

[0479](2R)-4-Benzyl-1-(3,5-dichlorobenzoyl)-2-[4-(trifluoromethyl)benzyl]piperazine

[0480] IR (Neat): 2942, 2809, 1641, 1070 cm⁻¹

[0481] NMR (DMSO-d₆δ): 2.00-4.90 (11H, m), 6.59 (1H, s), 7.10-7.70 (11H,m)

[0482] MASS: 507 (M+H)⁺

EXAMPLE 11

[0483] To a solution of (3R)-1-benzyl-3-(2-naphthylmethyl)piperazine(3.23 g) and triethylamine (4.3 ml) in dichloromethane (60 ml) was addeda solution of 3,5-dichlorobenzoyl chloride (6.0 g) in dichloromethane(10 ml) at 0° C. After stirring at room temperature for 3 hours, themixture was quenched with water and extracted three times with ethylacetate. The combined extracts were dried over magnesium sulfate, andevaporated under reduced pressure. The obtained residue was trituratedwith a mixture of dichloromethane and hexane to give (2R)-4-benzyl-1-(3,5-dichlorobenzoyl)-2-(2-naphthylmethyl)-piperazine.

[0484] NMR (DMSO-d₆, δ): 3.00-4.70 (9H, m), 6.66-7.86 (17H, m)

[0485] MASS: 689 (M+H)⁺ (free)

EXAMPLE 12

[0486] The following compound was obtained according to a similar mannerto that of Example 11.

[0487](2R)-4-Benzyl-1-(3,5-dichlorobenzoyl)-2-[(1H-indol-3-yl)methyl]piperazine

[0488] NMR (DMSO-d₆, δ): 2.10-4.60 (9H, m), 5.76 (2H, s), 6.70-7.68(13H, m)

[0489] MASS: 388 (M+H)⁺ (free)

EXAMPLE 13

[0490] The following compound was obtained according to a similar mannerto that of Example 1-(1)

[0491](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[3-(3-pyridyl)-2-propynyl]piperazinedihydrochloride

[0492] mp: 140-150° C.

[0493] [α]_(D) ^(25.9): −9.2° (C=0.50, MeOH)

[0494] IR (Kr): 3700-3200, 3000-2300, 1644, 1550, 1428, 1367, 1280 cm⁻¹

[0495] NMR (DMSO-d₆, δ): 2.20-5.20 (11H, m), 7.00-8.65 (14H, m)

[0496] MASS: 582 (M+H)⁺ (free)

[0497] Elemental Analysis Calcd. for C₃₁H₂₅F₆N₄O.2HCl.2.57H₂O:

[0498] C 54.85, H 4.62, N 6.00 Found: C 54.85, H 4.56, N 5.86

EXAMPLE 14

[0499] (1) Lindlar catalyst (Pd-CaCO₃-PbO) (86 mg) was added to asolution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthyimethyl)-4-[3-(3-pyridyl)-2-propynyl]piperazinein methanol (20 ml) The mixture was stirred for 2 hours under hydrogenat 25° C. and filtered. The filtrate was concentrated under reducedpressure and the resulting residue was chromatographed on silica gelusing a mixed eluent of hexane and ethyl acetate. The faster elutingfractions were collected, concentrated under reduced pressure andtreated with 4N hydrogen chloride in ethyl acetate to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[(2Z)-3-(3-pyridyl)-2-propenyl]piperazinedihydrochloride.

[0500] mp: 130-150° C.

[0501] [α]_(D) ^(27.5): −25.20° (C=0.21, MeOH)

[0502] IR (KBr): 3700-2200, 1646, 1280 cm⁻¹

[0503] NMR (DMSO-d₆, δ): 2.00-5.20 (11H, m), 6.30-8.90 (16H, m)

[0504] MASS: 584 (M+H)⁺ (free)

[0505] Elemental Analysis Calcd. for C₃₂H₂₇F₆N₃O.2HCl.3.7H₂O: C 53.19, H5.07, N 5.82 Found: C 53.19, H 5.21, N 5.61

[0506] (2) The slower eluting fractions were collected, concentratedunder reduced pressure and treated with 4N hydrogen chloride in ethylacetate to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[3-(3-pyridyl)propyl]piperazinedihydrochloride.

[0507] mp: 138-148° C.

[0508] [α]_(D) ^(26.4): −28.6° C. (C=0.25, MeOH)

[0509] IR (KBr): 3700-2200, 1646, 1280, 1135 cm⁻¹

[0510] NMR (DMSO-d₆, δ): 2.00-5.20 (15H, m), 6.30-8.90 (14H, m)

[0511] MASS: 586 (M+H)⁺ (free)

[0512] Elemental Analysis Calcd. for C₃₂H₂₉F₆N₃O.2HCl.2.9H₂O: C 54.10, H5.22, N 5.92 Found: C 54.11, H 5.37, N 5.70

EXAMPLE 15

[0513] A mixture of(2R)-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)piperazinehydrochloride (400 mg) and 4-(4-chloro-2-butynyl)morpholinehydrochloride (223 mg) in dried acetonitrile (4.0 ml) was stirred at 50°C. in the presence of powdered potassium carbonate (534 mg) andpotassium iodide (32 mg). After 3 hours, the reaction mixture wasfiltered and the insoluble material on the filter was washed withacetonitrile. The filtrate and the washing were combined and thenconcentrated in vacuo. The resulting residue was purified by columnchromatography on silica gel using a mixture of ethyl acetate andmethanol (10:1) as eluent. The product obtained was dissolved in ethylacetate and treated with 4N hydrogen chloride in erhyl acetate to give(2R)-1-(3,5-dichlorobenzoyl)-2-(3,4-dimerhylbenzyl)-4-(4-morpholino-2-butynyl)piperazinedihydrochloride (221 mg).

[0514] mp: 175° C. (dec.)

[0515] [α]_(D) ^(27.9): +6.80° (C=0.50, MeOH)

[0516] IR (Nujol): 2400, 1640, 1120 cm⁻¹

[0517] NMR (DNSO-d₆, δ): 2.10-4.40 (21H, m), 6.69 (3H, br), 7.06 (2H,br), 7.61 (1H, br)

[0518] MASS: 514 (M+H)⁺ (free)

[0519] Elemental Analysis Calcd. for C₂₈H₃₃Cl₂N₃O₂.2HCl.2H₂O: C 53.94, H6.30, N 6.74 Found: C 53.86, H 6.15, N 6.41

EXAMPLE 16

[0520] The following compounds were obtained according to a similarmanner to that of Example 15.

[0521] (1)(2R)-1-(3,5-Dichlorobenzoyl)-2-(3,4-dimethylbenzyl)-4-(4-thiomorpholino-2-butynyl)piperazinedihydrochloride

[0522] mp: 128° C. (dec.)

[0523] [α]_(D) ^(28.0): +6.40° (C=0.50, MeOH)

[0524] IR (Nujol): 2400, 1635 cm⁻¹

[0525] NMR (DMSO-d₆, δ): 2.05-4.70 (21H, m), 6.71 (3H, br), 7.04 (2H,br), 7.61 (1H, br)

[0526] MASS: 530 (M+H)⁺ (free)

[0527] Elemental Analysis Calcd. for C₂₈H₃₃Cl₂N₃OS.2HCl.2H₂O: C 52.59, H6.15, N 6.57 Found: C 52.72, H 6.19, N 6.35

[0528] (2)(2R)-1-(3,5-Dichlorobenzoyl)-2-(3,4-dimethylbenzyl)-4-[(E)-4-morpholino-2-butenyl]piperazinedihydrochloride

[0529] mp: >230° C.

[0530] [α]_(D) ^(25.3): +5.80° (C=0.50, MeOH)

[0531] IR (KBr): 3426, 2927, 1120, 970 cm⁻¹

[0532] NMR (DMSO-d₆, δ): 2.10-4.70 (23H, m), 6.17 (2H, br), 6.69 (3H,br), 7.07 (2H, br), 7.63 (1H, br)

[0533] MASS: 516 (M+H)⁺ (free)

[0534] Elemental Analysis Calcd. for C₂₈H₃₇Cl₄N₃O₂.0.5H₂O: C 56.20, H6.40, N 7.02 Found: C 56.20, H 6.29, N 6.89

[0535] (3)(2R)-1-(3,5-Dichlorobenzoyl)-2-[(1H-indol-3-yl)methyl]-4-(4-thiomorpholino-2-butynyl)piperazinedihydrochloride

[0536] mp: 175° C. (dec.)

[0537] [α]_(D) ^(26.0): +26.0° (C=0.50, MeOH)

[0538] IR (KBr): 3407, 2543, 1639 cm⁻¹

[0539] NMR (DMSO-d₆, δ): 2.60-5.10 (21H, m), 6.70-7.80 (8H, m), 11.02(1H, br s)

[0540] MASS: 541 (M+H)⁺ (free)

[0541] Elemental Analysis Calcd. for C₂₈H₃₂Cl₄N₄OS.1.5H₂O: C 52.43, H5.50, N 8.73 Found: C 52.34, H 5.60, N 8.42

[0542] (4)(2R)-1-(3,5-Dichlorobenzoyl)-2-[(1H-indol-3-yl)methyl]-4-(4-morpholino-2-butynyl)piperazinedihydrochloride

[0543] mp: 165° C. (dec.)

[0544] [α]_(D) ^(26.0): +27.500 (C=0.50, MeOH)

[0545] IR (KBr): 3407, 1639, 1126 cm⁻¹

[0546] NMR (DMSO-d₆, δ): 2.80-5.20 (21H, m), 6.70-7.85 (8H, m), 11.00(1H, br s)

[0547] MASS: 525 (M+H)⁺ (free)

[0548] Elemental Analysis Calcd. for C₂₈H₃₂Cl₄N₄O₂.3H₂O: C 51.55, H5.87, N 8.59 Found: C 51.59, H 5.52, N 8.33

[0549] (5)(2R)-1-(3,5-Dichlorobenzoyl)-2-(2-naphthylmethyl)-4-(4-thiomorpholino-2-butynyl)piperazinedihydrochloride

[0550] mp: 154° C. (dec.)

[0551] [α]_(D) ^(23.8): −14.10° C. (C=0.50, MeOH)

[0552] IR (KBr): 3417, 2933, 2537, 1641cm⁻¹

[0553] NMR (DMSO-d₆, δ): 2.70-5.20 (21H, m), 6.56 (1H, br), 7.08 (1H,br), 7.53 (4H, br), 7.39 (4H, br)

[0554] MASS: 552 (M+H)⁺ (free)

[0555] Elemental Analysis Calcd. for C₃₀H₃₃Cl₄N₃OS.1.5H₂O: C 55.22, H5.56, N 6.44 Found: C 55.09, H 5.64, N 6.31

[0556] (6)(2R)-1-(3,5-Dichlorobenzoyl)-2-(2-nanhthylmethyl)-4-(4-morpholino-2-butynyl)piperazinedihydrochloride

[0557] mp: 171° C. (dec.)

[0558] [α]_(D) ^(23.3): −15.10° (C=0.50, NeOH)

[0559] IR (KBr): 3407, 2931, 2561, 1641, 971 cm⁻¹

[0560] NMR (DMSO-d₆δ): 3.00-5.20 (21H, m), 6.56 (1H, br), 7.08 (1H, br),7.53 (4H, br), 7.89 (4H, br)

[0561] MASS: 536 (M+H)⁺ (free)

[0562] Elemental Analysis Calcd. for C₃₀H₃₃Cl₄N₃O₂.H₂O: C 57.43, H 5.62,N 6.70 Found: C 57.67, H: 5.68, N 6.31

[0563] (7)(2R)-1-(3,5-Dichlorobenzoyl)-2-[4-(trifluoromethyl)-benzyl]-4-(4-thiomorpholino-2-butynyl)piperazinedihydrochloride

[0564] mp: 172° C. (dec.)

[0565] [α]_(D) ^(25.4): +15.800 (C=0.50, MeOH)

[0566] IR (KBr): 3430, 2917, 2524, 1641, 1068 cm⁻¹

[0567] NMR (DMSO-d₆, δ): 2.70-5.20 (21H, m), 6.69 (1H, s), 7.10-7.30(2H, m), 7.63 (4H, br)

[0568] MASS: 570 (M+H)⁺ (free)

[0569] Elemental Analysis Calcd. for C₂₇H₃₀Cl₄F₃N₃OS.0.5H₂O: C 49.71, H4.79, N 6.44 Found: C 49.37, H 5.09, N 6.30

[0570] (8)(2R)-1-[3,5-Dichlorobenzoyl)-2-[4-(trifluoromethyl)-benzyl]-4-(4-morpholino-2-butynyl)piperazinedihydrochloride

[0571] mp: 186° C. (dec.)

[0572] [α]_(D) ^(25.4): +17.500 (C=0.50, MeOH)

[0573] IR (KBr): 3421, 2935, 2553, 1644, 1068 cm⁻¹

[0574] NMR (DMSO-d₆, δ): 2.80-5.20 (21H, m), 6.72 (1H, s), 7.10-7.40(2H, m), 7.64 (4H, br)

[0575] MASS: 554 (M+H)⁺ (free)

[0576] Elemental Analysis Calcd. for C₂₇H₃₀Cl₄F₃N₃O₂.0.5H₂O: C 50.96, H4.91, N 6.60 Found: C 50.57, H 5.05, N 6.52

EXAMPLE 17

[0577] A mixture of(2R)-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)piperazinehydrochloride (300 mg), 3-bromo-1-propanol (121 mg), potassium carbonate(251 mg) and potassium iodide (24 mg) in dried acetonitrile (3 ml) wasstirred at 50° C. for 10 hours. After being cooled to room temperature,the reaction mixture was filtered and the filtrate was concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel using ethyl acetate as eluent to give(2R)-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)-4-(3-hydroxypropyl)piperazine as a syrup.Methanesulfonyl chloride (58 mg) was added to an ice-cooled solution ofthe alcohol obtained at above procedure (210 mg) and triethylanine (97.6mg) in dichloromethane (4 ml) over 1.5 hours. After being stirred for 1hour, the reaction mixture was washed with saturated sodium bicarbonatesolution, dried over magnesium sulfate and evaporated under reducedpressure to give the corresponding mesylate. A mixture of the mesylateobtained by the above procedure, 4-aminomorpholine (59.1 mg) andtriethylamine (73.2 mg) in methanol (4 ml) was stirred under reflux for4 hours. The reaction mixture was concentrated under reduced pressureand the residue was purified bv column chromatography on silica gelusing ethyl acetate as eluent and treated with 4N hydrogen chloride inethyl acetate solution to give(2R)-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)-4-(N-morpholino-3-aminocropyl)piperazinedihydrochloride.

[0578] mp: 71° C. (dec.)

[0579] [α]_(D) ^(22.5): +1.000 (C=0.50, MeOH)

[0580] IR (Nujol): 3400, 2950, 1640, 1100 cm ⁻¹

[0581] NMR (DMSO-d₆, δ): 2.10-4.70 (23H, m) 6.68 (3H, br), 7.06 (2H,br), 7.63 (1H, br)

[0582] MASS: 519 (M+H)⁺ (free)

[0583] Elemental Analysis Calcd. for C₂₇H₃₈Cl₄N₄O₂.2.5H₂O: C 50.87, H6.80, N 8.79 Found: C 51.03, H 7.15, N 8.84

EXAMPLE 18

[0584] Under nitrogen atmosphere, to a mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine(315 mg) and 3-(1-methyl-1H-imidazol-4-yl)propanal (98 mg) indichloromethane (6 ml) was added sodium triacetoxyborohydride (225 mg)and stirred at room temperature. After 4 hours, aqueous sodiumbicarbonate solution was added to the mixture and the mixture wasstirred for several minutes. The organic layer was separated, dried oversodium sulfate and evaporated under reduced pressure. The resultingresidue was purified by column chromatography on silica gel usingdichloromethanemethanol (10:1) as eluent and treated with 4N hydrogenchloride in ethyl acetate solution to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(1-methyl-1H-imidazol-4-yl)propyl]piperazinedihydrochloride (187.1 mg).

[0585] mp: 91° C. (dec.)

[0586] [α]_(D) ^(24.2): −11.20° (C=0.50, MeOH)

[0587] IR (Nujol): 1640 cm⁻¹

[0588] NMR (DMSO-d₆, δ): 2.00-5.20 (21H, m), 6.67 (!H, br s), 6.90-7.20(2H, m), 7.44 (!H, br s), 7.56 (1H, br s), 7.67 (1H, br s), 8.18 (1H, brs), 9.03 (1H, br s)

[0589] MASS: 567 (M+H)⁺ (free)

[0590] Elemental Analysis Calcd. for C₂₉H₃₄Cl₂F₆N₄O.3.5H₂O: C 49.58, H5.88, N 7.97 Found: C 49.71, H 5.90, N 7.79

EXAMPLE 19

[0591] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine(500 mg), 2-(2-chloroethoxy)-ethanol (168 mg), potassium carbonate (233mg) and potassium iodide (56 mg) in N,N-dimethylformamide (2 ml) washeated with stirring at 50° C. for 17 hours, 60° C. for 13 hours and 70°C. for 1 hour. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with brine and driedover magnesium sulfate. After evaporation of the solvent, the resultingresidue was purified by column chromatography on silica gel usingdichloromethane-methanol (10:1) as eluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(2-hydroxyethoxy)ethyl]piperazine(359 mg).

[0592] IR (Neat): 3450, 1640, 1440, 1280, 1130 cm⁻¹

[0593] NMR (DMSO-d₆, δ): 2.03-4.93 (23H, m), 6.60-8.20 (6H, m)

[0594] MASS: 533 (M+H)⁺

EXAMPLE 20

[0595] To a stirred solution of oxalyl chloride (151 mg) indichloromethane (3 ml) was added dropwise a solution ofdimethylsulfoxide (123 mg) in dichloromethane (0.25 ml) at −78° C. undernitrogen atmosphere. After 15 minutes,(2R)-1-[3,5-bis(trifluoromethyl)benzoyl-]-2-(3,4-dimethylbenzyl)-4-[2-(2-hydroxyethoxy)ethyl]piperazine(317 mg) was added at the same temperature. After 15 minutes, theresulting mixture was stirred at −45° C. for 1 hour. Triethylamine (446mg) was added at −45° C., and the whole was stirred at 0° C. for 20minutes and then treated with aaueous solution of ammonium chloride (2ml). The organic layer was separated and dried over magnesium sulfate.After evaporation of the solvent, the resulting residue was purified bycolumn chromatography on silica gel using ethyl acetate as eluent toafford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(formylmethoxy)ethyl]piperazine(171 mg).

[0596] IR (Neat): 3450, 1740, 1640, 1440, 1280, 1130 cm⁻¹

[0597] NMR (DMSO-d₆, δ): 1.91-4.91 (22H, m,), 6.53-8.20 (6H, m)

[0598] MASS: 351 (M+H)⁺

EXAMPLE 21

[0599] To a stirred mixture of 3,3-dimethylmorpholine hydrochloride (63mg) and triethylamine (42 mg) in dichloromethane (5 ml) were added(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyyl)-4-[2-(formylmethoxy)ethyl]piperazine(200 mg) and sodium triacetoxyborohydride (120 mg) at room temperature.The resulting mixture was stirred for 1 hour and then treated withaqueous sodium bicarbonate solution. The organic layer was separated anddried over magnesium sulfate. After evaporation of the solvent, theresidue was purified by column chromatography on silica gel usingdichloromethanemethanol (10:1) as eluent and treated with 4N hydrogenchloride in ethyl acetate to give(2R)-1-[3,5-bis(trifluoromerhyl)benzoyl]-2-134-dimethylbenzyl)-4-[2-2-(3,3-dimethylmorpholino)ethoxy]ethyl]piperazinedihydrochioride (193 mg) as a powder.

[0600] [α]_(D) ²³: −18.20° (C=0.50, MeOH)

[0601] IR (Neat): 3450, 2600, 1640, 1430, 1280, 1140 cm ⁻¹

[0602] NMR (DMSO-d₆, δ): 1.33 (6H, s), 2.04-5.23 (29H, m), 6.60-8.26(6H, m)

[0603] MASS: 630 (M+H)⁺ (free)

[0604] Elemental Analysis Calcd. for C₃₂H₄₁F₆N₃O₃.2HCl.3.32H₂O: C 50.41,H 6.56, N 5.51 Found: C 50.41, H 6.29, N 5.31

EXAMPLE 22

[0605] The following compound was obtained according to a similar mannerto that of Exampne 21.

[0606](2R)-1-[(3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(2-morpholinoethoxy)ethyl]piperazinedihydrochloride

[0607] [α]_(D) ²³: −21.4° (C=0.50, MeOH)

[0608] IR (Neat): 3450, 2600, 1640, 1430, 1280, 1180, 1135 cm⁻¹

[0609] NMR (DMSO-d₆, δ): 2.08-5.20 (31H, m), 6.60-8.24 (6H, m)

[0610] MASS: 602 (M+H)⁺ (free)

[0611] Elemental Analysis Calcd. for C₃₀H₃₇F₆N₃O₃.2HCl.2.66H₂O: C 49.87,H 6.18, N 5.82 Found: C 49.87, H 6.25, N 5.65

EXAMPLE 23

[0612] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl-4-(3-methylsulfonyloxypropyl)-piperazine(250 mg), 4-aminothiomorpholine (90 mg) and sodium carbonate (180 mg) inmethanol (5 ml) was stirred at reflux temperature for 3 hours. Thereaction mixture was filtered and the filtrate was evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel using ethyl acetate-methanol (10:1) as eluent and treatedwith 4N hydrogen chloride in ethyl acetate (3 ml) to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)-methyl]-4-[3-(thiomorcholinoamino)propyl]piperazinedihydrochloride (62 mg) as a powder.

[0613] [α]_(D) ²⁷: −5.80° (C=0.50, MeOH,

[0614] IR (Neat): 3300, 2500, 1630, 1420, 1275, 1130 cm⁻¹

[0615] NMR (DMSO-d₆, δ): 2.03-5.20 (23H, m), 6.60-8.24 (8H, m), 10.95(1H, s)

[0616] MASS: 614 (M+H)⁺ (free)

[0617] Elemental Analysis Calcd. for C₂₉H₃₅Cl₂F₆N₅OS.3H₂O: C 47.10, H5.37, N 8.88 Found: C 47.03, H 5.58, N 9.46

EXAMPLE 24

[0618] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-methylsulfonyloxyethyl)piperazine(200 mg), 3-hydroxymethylpiperidine (44 mg) and triethylamine (73 mg) inmethanol (5 ml) was stirred at reflux temperature for 2.5 hours. Thereaction mixture was evaporated under reduced pressure and the residuewas partitioned between ethyl acetate (30 ml) and water (10 ml). Theorganic layer was dried over magnesium sulfate and then evaporated underreduced pressure. The obtained residue was purified by columnchromatography on silica gel using dichloromethanemethanol (10:1) aseluent and treated with 4N hydrogen chloride in ethyl acetate (0.2 ml)to give(2R)-1-[3,5-bis-(tritfiuoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(3-hydroxymethylpiperidino)ethyl]piperazinedihydrochloride (85 mg).

[0619] [α]_(D) ²⁵: −5.30° (C=0.50, MeOH)

[0620] IR (Neat): 3350, 2500, 1640, 1420, 1280, 1180, 1130 cm⁻¹

[0621] NMR (DMSO-d₆, δ): 1.0-5.20 (30H, m), 6.66-8.31 (6H, m)

[0622] MASS: 586 (M+n)⁺ (free)

[0623] Elemental Analysis Calcd. for C₃₀H₃₉Cl₂F₆N₃O₂.3H₂O: C 50.56, H6.36, N 5.90 Found: C 50.58, H 6.24, N 5.87

EXAMPLE 25

[0624] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-chloro-2-butynyl)-2-(2-naphthylmethyl)piperazine(600 mg), 3,3-dimethylmorpholine hydrochloride (197 mg) and potassiumcarbonate (420 mg) in N,N-dimethylformamide (10 ml) was stirred at roomtemperature in the presence of potassium iodide (10 mg) for 2 days. Thereaction mixture was partitioned between ethyl acetate (50 ml) and water(100 ml) and the organic layer was separated, washed with brine anddried over magnesium sulfate. After evaporation of the solvent, theresidue was purified by column chromatography on silica gel using amixture of ethyl acetate-hexane (10:1). The obtained product wasdissolved in ethyl acetate and treated with 4N hydrogen chloride inethyl acetate to give(2R)-1-[3,-5-bis(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-(2-naphthylmethyl)piperazinedihydrochloride (360 mg).

[0625] IR (KBr): 3401, 2929, 2578, 2512, 1644, 1284, 1135 cm⁻¹

[0626] NMR (DMSO-d₆, δ): 1.32 (3H, s), 1.39 (3H, s), 3.0-5.4 (19H, m),7.0-8.2 (10H, m)

[0627] MASS: 632 (M+H)⁺ (free)

[0628] Elemental Analysis Calcd. for C₃₄H₃₇Cl₂F₆N₃O₂.2.5H₂O: C 54.48, H5.65, N 5.61 Found: C 54.25, H 5.53, N 5.39

EXAMPLE 26

[0629] Acetic anhydride (209 mg) was added to formic acid (94 mg). Theresulting mixture was allowed to warm at 50° C. for 30 minutes and thenadded to(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(morpholinoamino)propyl]piperazine(200 mg) at room temperature. The whole was stirred overnight and thenevaporated under reduced pressure. The obtained residue was dissolved inethyl acetate and treated with 4N hydrogen chloride in ethyl acetate(0.2 ml) to give(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)-4-[(3-(N-formylmorpholinoamino)propyl]piperazinehydrochloride (112 mg).

[0630] [α]_(D) ²³: −16.3° (C=0.50, MeOH)

[0631] IR (Neat) 3450, 2800, 2620, 1660, 1430, 1280, 1185, 1140 cm⁻¹

[0632] NMR (DMSO-d₆, δ): 1.94-5.16 (29H, m), 6.62-8.35 (7H, m)

[0633] MASS: 615 (M+H)⁺ (free)

[0634] Elemental Analysis Calcd. for C₃₀H₃₇ClF₆N₄O₃.1.36H₂O: C 53.34, H5.93, N 8.29 Found: C 53.33, H 5.79, N 8.06

EXAMPLE 27

[0635] To a mixture of(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)piperazine(3.71 g) and 4-formyl-1-(trichenylmethyl)pyrazole (3.66 g) in1,2-dichloroethane (80 ml) was added sodium triacetoxyborohydride (2.86g). After stirring at room temperature for 3 hours, aqueous sodiumbicarbonate solution was added to the mixture and the mixture wasextracted with ethyl acetate. The extract was washed with brine, driedover magnesium sulfate and evaporated under reduced pressure. Theresulting residue was dissolved in dichloromethane (40 ml) and added toa mixture of trifluoroacetic acid (30 ml) and anisole (15 ml). Afterstirring for 7.5 hours at room temperature, the mixture was quenchedwith 10% sodium hydroxide (150 ml) and aqueous sodium bicarbonate andextracted with dichloromethane. The extract was washed with aauecussodium bicarbonate solution and brine successively, dried over magnesiumsulfate, and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel using a mixture of ethyl acetateand hexane (3:7) to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-pyrazolylmethyl)piperazine(2.84 g).

[0636] NMR (DMSO-d₆, δ): 2.04-2.14 (6H, m), 2.60-4.76 (11H, m),6.49-6.54 (1H, m), 6.86-6.96 (2H, m), 7.45 (2H, br s), 7.64-7.68 (2H,m), 8.14 (1H, m)

[0637] MASS: 525 (M+H)⁺

EXAMPLE 28

[0638] Potassium carbonate (158 mg) and 2-bromoethanol (0.045 ml) wereadded to a solution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-pyrazolylmethyl)piperazine(300 mg) in N,N-dimethylformamide (3 ml) at room temperature withstirring. After stirring at 100° C. for 5 hours. the reaction mixturewas poured into water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over magnesium sulfate, andevaporated under reduced pressure. The obtained residue was nurified bycolumn chromatography (30 ml) on silica gel using a mixture of ethylacetate and hexane (3:7) to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methyl]piperazine(255.2 mg).

[0639] IR (KBr): 1640 cm⁻¹

[0640] NMR (DMSO-d₆, δ): 2.04-2.15 (6H, m), 2.60-4.80 (11H, m) ,3.67-3.75 (2H, m), 4.10 (2H, t, J=5.7Hz), 4.86 (1H, t, J=5.3Hz),6.50-6.56 (1H, m), 6.90-6.98 (2H, m), 7.36 (1H, br s), 7.43 (1H, br s),7.61 (1H, br s), 7.67 (1H, br 5), 8.13 (1H, br s)

[0641] MASS: 569 (M+H)⁺

EXAMPLE 29

[0642] To a solution of(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)-4-[[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methyl]piperazlne(152 mg) in ethyl acetate (2 ml) was added triethylamine (0.048 ml) andmethanesulfonyl chloride (0.027 ml) at room temperature. After stirringfor 10 minutes, the mixture was quenched with water and extracted withethyl acetate. The combined extracts were washed with water and brinesuccessively, dried over magnesium sulfate, and evaporated under reducedpressure. The obtained residue was dissolved with N,N-dimethylformamide(2 ml) and added morpholine (0.028 ml), potassium carbonate (74 mg) andpotassium iodide (13 mg). After stirring at 70° C. for 6 hours, themixture was auenched with water and extracted with ethyl acetate. Thecombined extracts were washed with water and brine successively, driedover magnesium sulfate, and evaporated under reduced pressure. Theobtained residue was dissolved in ethyl acetate and treated with 4Nhydrogen chloride in ethyl acetate (0.2 ml) at room temperature. Themixture was added hexane, filtered, and dried over reduced pressure togive(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)-4-[[l-(2-morpholinoethyl)-1H-pyrazol-4-yl]methyl]piperazinedihydrochloride (188.7 mg) as a solid.

[0643] mp: 115-116° C.

[0644] [α]_(D) ²⁵: −9.70° (C=0.50, MeOH)

[0645] IR (KBr): 1640 cm⁻¹

[0646] NMR (DMSO-d₆, δ): 2.06-2.16 (6H, m), 2.85-5.00 (23H, m),6.60-6.60-6.64 (1H, m), 6.91-7.08 (2H, m), 7.57 (1H, s), 7.74 (1H, brs), 7.78 (1H, br s), 8.10 (1H, br s), 8.18 (1H, br s)

[0647] MASS: 638 (M+H)⁺ (free)

EXAMPLE 30

[0648] As solution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-chloro-2-butynyl)-2-(2-naphthylmethyl)piperazine(200 mg), 3-(aminomethyl)pyridine (47 mg), and triethylamine (0.08 ml)in acetonitrile (2 ml) was stirred under reflux for 3 hours andevaporated under reduced pressure. The obtained residue was purified bycolumn chromatography on silica gel (10 ml) usingdichloromethane-methanol (30:1) as eluent. The obtained oil wasdissolved in ethyl acetate and treated with a solution of 4N hydrogenchloride in ethyl acetate. The mixture was evaporated under reducedpressure to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(3-pyridylmethylamino)-2-butynyl]-2-(29-nachthylmethyl)piperazinetrihydrochloride (60 mg) as a powder.

[0649] [α]_(D) ²⁹: −20.80° (C=0.25, MeOH)

[0650] IR (Neat): 3650-3100, 2750-1950, 1630, 1273, 1122 cm⁻¹

[0651] NMR (DMSO-d₆, δ): 2.60-5.30 (16H, m), 7.00-9.10 (14H, m)

[0652] MASS: 625 (M+H)⁺ (free)

[0653] Elemental Analysis Calcd. for C₃₄H₃₃Cl₃F₆N₄O.3.3H₂O: C 51.43, H5.03, N 7.06 Found: C 51.42, H 4.91, N 6.78

EXAMPLE 31

[0654] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-chloro-2-butynyl)-2-(2-naphthylmethyl)piperazine(300 mg), cis-2,6-dimethylmorpholine (94 mg) and powdered potassiumcarbonate (210 mg) in dry N,N-dimethylformamide (5 ml) was stirred atroom temperature overnight. The reaction mixture was poured into water(50 ml) and extracted with ethyl acetate. The extract was washed withbrine and dried over magnesium sulfate. After evaporation of thesolvent, the obtained residue was purified by column chromatography onsilica gel using a mixture of ethyl acetate and hexane (4:1) as eluent.The obtained product was dissolved in ethyl acetate and treated with 4Nhydrogen chloride in ethyl acetate to give(2R)-1-(3,5-bis(tri-fluoromethyl)benzoyl]-4-[4-(cis-2,6-dimethylmorpholino)-2-butynyl]-2-(2-naphthylmethyl)piperazinedihydrochlorlde (170 mg).

[0655] IR (KBr): 3428, 2931, 2559, 1644, 1432, 1282, 1184 cm⁻¹

[0656] NMR (DMSO-d₆, δ):1.13 (3H, s) 1.16 (3H, s), 2.60-5.40 (21H, m),7.00-8.15 (10H, m)

[0657] MASS: 632 (M+H)⁺ (free)

[0658] Elemental Analysis Calcd. for C₃₄H₃₇Cl₂F₆N₃O₂.2H₂O: C 55.14, H5.58, N 5.67 Found: C 54.89, H 5.59, N 5.31

EXAMPLE 32

[0659] The following compound was obtained according to a similar mannerto that of Example 31.

[0660]1,3-[Bis(trifluoromethyl)benzoyl]-4-[4-(2-methylthiazol-4-yl)methyl]-2-[(1H-indol-3-yl)methyl]piperazinehydrochloride

[0661] NMR (DMSO-d₆, δ): 2.65 (3H, s), 3.00-5.20 (11H, m), 6.80-8.24(9H, m), 10.93 (1H, br d)

[0662] MASS: 567 (M+H)⁺ (free)

EXAMPLE 33

[0663] To a stirred mixture of(2R)-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)piperazine(943 mg) and potassium carbonate (880 mg) in dimethylformamide (10 ml)was added propargyl bromide (0.2 ml) at room temperature. After 1 hour,the reaction mixture was poured into water (100 ml) and extracted withethyl acetate. The extract was washed with brine and concentrated underreduced pressure. The obtained residue was purified by columnchromatography on silica gel using a mixture of hexane and ethyl acetate(5:1) as eluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-propargylpiperazine(1.09 g) as an oil.

[0664] NMR (DMSO-d₆, δ): 2.00-2.20 (6H, m), 2.20-5.00 (12H, m),6.60-8.20 (6H, m)

[0665] MASS: 483 (M+H)⁺

EXAMPLE 34

[0666] A mixture of (2R)-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl-4-propargylpiperazine(286 mg), (3S)-3-isopropylmorpholine hydrochloride (118 mg) andN,N-diisopropylamine (92 mg) in dioxane (3 ml) was stirred at roomtermperazure. Paraformaldehyde (22 mg) and copper(I) chloride (10 mg)were added and the whole was stirred for 30 minutes and then heated at80° C. for 4 hours. The reaction mixture was filtered and the filtratewas concentrated under reduced pressure. The obtained residue waspurified by column chromatography, on silica gel using a mixture ofhexane and ethyl acetate (1:1) as eluent. The obtained product wasdissolved in ethyl acetate and treated with 4N hydrogen chloride inethyl acetate to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3-isopropylmorpholino)-2-butynyl]-2-(3,4-dimethylbenzyl)piperazinedihydrochloride (190 mg).

[0667] IR (KBr): 3438, 2971, 2551, 1644, 1438, 1282, 1216, 1135 cm⁻¹

[0668] NMR (DMSO-d₆, δ): 1.01 (6H, d, J=6.8Hz), 2.09-2.17 (6H, m), 2.36(1H, m), 2.60-5.30 (22H, m), 6.60-8.30 (6H, m)

[0669] MASS: 624 (M+H)⁺ (free)

EXAMPLE 35

[0670] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-chloro-2-butenyl)-2-(3,4-dimethylbenzyl)piperazine(150 mg), (3S)-3-isopropylmorpholine hydrochloride (47 mg) and powderedpotassium carbonate (117 mg) in dry N,N-dimtethylformamide (1 ml) wasstirred at 50° C. for 1.5 hours. The reaction mixture was poured intowater (10 ml) and extracted with ethyl acetate. The extract was washedwith brine and dried over magnesium sulfate. After evaporation of thesolvent, the obtained residue was purified by column chromatography onsilica gel using ethyl acetate as eluent. The obtained product wasdissolved in ethyl acetate and treated with 4N hydrogen chloride inethyl acetate to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3-isopropylmorpholino)-2-butenyl]-2-(3,4-dimethylbenzyl)-piperazinedihydrochlorlde (110 mg).

[0671] IR (KBr): 3430, 2971, 2661, 1644, 1434, 1280, 1135, 985, 680 cm⁻¹

[0672] IR (DMSO-d₆, δ): 1.01 (6H, m), 2.00-2.20 (6H, m), 2.40 (1H, m),2.60-5.20 (24H, m), 6.60-8.20 (6H, m)

[0673] MASS: 626 (M+H)⁺ (free)

[0674] Elemental Analysis Calcd. for C₃₃H₄₃Cl₂F₆N₃O₂.3H₂O: C 52.66, H6.56, N 5.58 Found: C 52.45, H 6.55, N 5.49

EXAMPLE 36

[0675] To a stirred solution of(2R)-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((3R,3S)-3-hydroxymethylpiperidino)ethyl]piperazine (133 mg) inN,N-dimethylformamide (1 ml) was added 60% sodium hydride (109 mg) atice-salt bath temperature. A solution of ethyl iodide (53 mg) inN,N-dimethylformamide (0.5 ml) was added and the whole was stirred for15 minutes and then at room temperature for 1 hour. The reaction mixturewas poured into water (20 ml) and extracted with ethyl acetate. Theextract was washed with brine and concentrated under reduced pressure.The obtained residue was purified by column chromatographt on silica gelusing a mixture of dichloromethane and methanol (10:1) as eluent. Theobtained product was dissolved in ethyl acetaze and treated with 4Nhydrogen chloride in ethyl acetate to give(2R)-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((3R,3S)-3-ethoxymethylpiperidino)-ethyl]piperazinedihydrochoride (101 mg).

[0676] [α]_(D) ²³: −8.0 (C=0.50, MeOH)

[0677] IR (KBr): 3400, 2630, 2540, 1645, 1435, 1280, 1180, 1135 cm⁻¹

[0678] NMR (DMSO-d₆, δ): 0.72-5.24 (32H, m), 1.12 (3H, t), 6.62-8.26(6H, m)

[0679] MASS: 614 (M+H)⁺ (free)

EXAMPLE 37

[0680] The recuisite mesylate was prepared by the treatment of(2R)-1-[3,5-bis(trrfluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-hydroxyethyl)piperazinewith methanesulfonyl chloride. A mixture of the mesylate (200 mg) and4-hydroxymethylpiperidine hydrochloride (66 mg) in methanol (1 ml) washeated at reflux in the presence of potassium carbonate (150 mg). After3 hours, the reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby column chromatography on silica gel using a mixture ofdichloromethane and methanol (5:1) as eluent. The obtained product wasdissolved in ethyl acetate and treated with 4N hydrogen chloride inethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-(4-hydroxymethylpiperidino)ethyl]-2-(3,4-dimiethylbenzyl)-piperazinedihydrochloride (32 mg).

[0681] [α]_(D) ²⁶: −5.8° (C=0.50, MeOH)

[0682] IR (KBr): 3370, 2600, 16415, 1430, 1280, 1180, 1140 cm⁻¹

[0683] NMR (DMSO-d₆, δ): 1.40-5.24 (30H, m), 6.60-8.24 (6H, m), 8.45(1H, s)

[0684] MASS: 586 (M+H)⁺ (free)

[0685] Elemental Analysis Calcd. for C₃₀H₃₇F₆N₃O₂.2HCl.4.85H₂O: C 48.36,H 6.57, N 5.64 Found: C 48.31, H 5.95, N 4.96

EXAMPLE 38

[0686] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-chloro-2-butynyl)-2-(3,4-dimethylbenzyl)piperazine(150 mg), (3S)-3-ethylmorpholine hydrochloride (47 mg) and powderedpotassium carbonate (117 mg) in dry N,N-dimethylformamide (1 ml) wasstirred at 50° C. for 1.5 hours. The reaction mixture was poured intowater (10 ml) and extracted with ethyl acetate. The extract was washedwith brine and dried over magnesium sulfate. After evaporation of thesolvent, the obtained residue was purified by column chromatography onsilica gel using ethyl acetate as eluent. The obtained product wasdissolved in ethyl acetate and treated with 4N hydrogen chloride inethyl acetate to give (2R)-1-[3,5-bi(trifluoromethyl)benzoyl]-4-[-((3S)-3-ethylmorpholino)-2-butynyl]-2-(3,4-dimethylbenzyl)piperazinedihydrochloride (177 mg).

[0687] [α]_(D) ²⁶: 4.8° (C=0.50, MeOH)

[0688] IR (KBr): 3430, 2580, 1645, 1435, 1280, 1180, 1135 cm⁻¹

[0689] NMR (DMSO-d₆, δ): 1.27 (3H, t), 1.45-5.20 (28H, m), 6.64-8.28(6H, m)

[0690] MASS: 610 (M+H)⁺ (free)

[0691] Elemental Analysis Calcd. For C₃₂H₃₇F₆N₃O₂.2HCl.3.5H₂O: C 51.55,H 6.22, N 5.64 Found: C 51.61, H 6.02, N 5.60

EXAMPLE 39

[0692] The requisite mesylate was oretared by the treatment of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-hydroxyethyl)piperazine(150 mg) with methanesulfonyl chloride (37 mg). A mixture of themesylate and (3S)-3-ethylmorpholine hydrochloride (51 mg) inN,N-dimethylformamide (1 ml) was heated at 50° C. in the presence ofpotassium carbonate (85 mg). After 2 hours, the reaction mixture waspoured into water (10 ml) and extracted with ethyl acetate. The extractwas washed with brine and dried over magnesium sulfate. Afterevaporation of the solvent, the obtained residue was purified by columnchromatography on silica gel using ethyl acetate as eluent. The obtainedproduct was dissolved in ethyl acetate and treated with 4N hydrogenchloride in ethyl acezate to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-((3S)-3-ethylmorpholino)ethyl]-2-(3,4-dimethylbenzyl)piperazinedihydrochloride (45 mg).

[0693] [α]_(D) ²⁴: 1.60° (C=0.50, MeOH)

[0694] IR (KBr): 3430, 2610, 1645, 1435, 1280, 1180, 1135. cm⁻¹

[0695] NMR (DMSO-d₆, δ): 0.95 (3H, s), 1.16-5.20 (28H, m), 6.64-8.24(6H, m)

[0696] MASS: 586 (M+H)⁺ (free)

[0697] Elemental Analysis Calcd. for C₃₀H₃₇F₆N₃O₂.2HCl.1.8H₂O: C 52.15,H 6.21, N 6.08 Found: C 52.15, H 6.42, N 6.00

EXAMPLE 40

[0698] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(2-methylsulfonyloxyethyl)-2-(2-naphthylmethyl)piperazine(200 mg), 3-(N-methylaminomethyl)pyridine dihydrochloride (73 mg) andtriethylamine (120 mg) in dry methanol (5 ml) was refluxed for 4 hours.The reaction mixture was concentrated under reduced pressure and theresulting residue was partitioned between ethyl acetate and aqueoussodium bicarbonate solution. The organic layer was washed with brine anddried over magnesium sulfate. After evaporation of the solvent, theresidue was purified by column chromatography on silica gel using amixture of ethyl acetate and methanol (10:1) as eluent to afford an oilyproducts which was treated with 4N hydroaen chloride in ethyl acetate(0.5 ml) to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-[(N-methyl-N-(3-pyridylmethyl)amino]ethyl]-2-(2-naphthylmethyl)piperazinedihydrochloride (78 mg).

[0699] [α]_(D) ²⁵: −12.9° (C=0.50, MeOH)

[0700] IR (KBr): 3410, 2600, 1640, 1430, 1280, 1180, 1135 cm⁻¹

[0701] NMR (DMSO-d₆, δ): 2.40-5.28 (15H, m), 2.74 (3H, s), 7.00-9.10(14H, m)

[0702] MASS: 615 (M+H)⁺ (free)

[0703] Elemental Analysis Calcd. for C₃₃H₃₂F₆N₄O.2HCl.4.6H₂O: C 51.45, H5.65, N 7.27 Found: C 51.40, H 5.37, N 7.07

EXAMPLE 41

[0704] The following comcound was obtained according to a similar mannerzo that of Example 40.

[0705](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl]-piperazinedihydrochloride

[0706] [α]_(D) ²⁴: −0.8° (C=0.50, MeOH)

[0707] IR (KBr): 3400, 2600, 1640, 1280, 1180, 1135 cm⁻¹

[0708] NMR (DMSO-d₆, δ): 1.12-5.20 (15H, m), 2.84 (3H, s), 6.63-9.00(12H, m), 10,95 (1H, s)

[0709] MASS: 604 (M+H)⁺

[0710] Elemental Analysis Calcd. for C₃₁H₃₁5F₆N₅O.2HCl.4 5H₂O: C 49.15,H 5.59, N 9.24 Found: C 49.19, H 5.41, N 9.08

EXAMPLE 42

[0711] To a stirred mixture of(2R)-1-(3,5-[bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[N-(1-piperazinyl)carbamoylmethyl]piperazinedihydrochloride (500 mg) and triethylamine (302 mg) in tetrahydrofuran(10 ml) was added a solution of benzyl 4-bromobutanoare (192 mg) intetrahydrofuran (2 ml) at room temrerature for 24 hours. As a part ofstarting material remained, the reaction mixture was filtered and thefiltrate was concentrated under reduced pressure. To the resultingresidue were added benzyl 4-bromobutanoate (192 mg), potassium carbonate(310 mg) and N,N-dimethylformamide (2 ml). The whole was stirred at roomtemperature for 7 hours and then diluted witn ethyl acetate andfiltered. The filtrate was washed with brine and dried over magnesiumsulfate. After evaporation of solvents the residue was purified bycolumn chromatography on a silica gel using a mixture of ethyl acetateand methanol (5:1) as eluent to afford(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[N-[4-(3-benzyloxycarbonylpropyl)piperazin-1-yl-carbamoylmethyl]-2-[(1H-indol-3-yl)methylpiperazine(296 mg).

[0712] IR (Neat): 3250, 1720, 1670, 1630, 1430, 1350, 1270, 1112 cm⁻¹

[0713] NR (CDCl₃, δ): 1.60-3.66 (25H, m), 5.10 (2H, s), 6.80-7.86 (8H,m), 7.32 (5H, s), 8.21 (1H, s)

[0714] MASS: 773 (M+H)⁺

EXAMPLE 43

[0715] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[N-[4-(3-benzyloxycarbonylpropyl)piperazin-1-yl]-carbamoylmethyl]-2-[(1H-indol-3-yl)methyllpiperazine(1.3 g), ammonium formate (265 mg) and 10% palladium on activated carbon(130 mg) in water (2.5 ml) and ethanol (25 ml) was heated at 70° C. withstirring under a nitrogen atmosphere. After 1 hour, the reaction mixturewas filtered and the filtrate was concentrated under reduced pressure.The product was triturated with ethyl ether to give(2R)-1-[3,5-bis(trifluoromerthyl)benzovyl]-4-N-[4-(3-carboxypropyl)-piperazin-1-yl]carbamoylmethyl]-2-[(1H-indol-3-yl)methyl[-piperazine(1.19 g) as a powder.

[0716] [α]_(D) ²⁸: −18.60° (C=0.50, MeOH)

[0717] IR (Neat): 3200, 1680, 1620, 1425, 1275, 1120 cm ¹

[0718] NMR (CDCl₃, δ): 1.72-4.60 (25H, m), 6.71-7.93 (8H, m)

[0719] MASS: 683 (M+H)⁺

EXAMPLE 44

[0720] The following compounds were obtained according to a similarmanner to that of Example 5-(1).

[0721] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[(2E)-3-[(3R)-4-(tert-butoxycarbonyl)morpholin-3-yl]-2-propenyl]-2-(3,4-dimethylbenzyl)piperazine

[0722] IR (Neat): 2973, 1697, 1645 cm⁻¹

[0723] NMR (CDCl₃, δ): 1.39 (9H, s), 2.00-2.16 (6H, m), 2.48-5.00 (18H,m), 5.40-5.80 (2H, m), 6.60-6.80 (1H, m), 6.90-7.20 (2H, m), 7.30-7.70(3H, m), 8.13 (1H, br s)

[0724] MASS: 670 (M+H)⁺

[0725] (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(2E)-3-[(2R,2S)-4-(tert-butoxycarbonyl)morpholin-2-yl]-2-propenyl]-2-(3,4-dinethylbenzyl)piperazine

[0726] NMR (DMSO-d₆, δ): 1.41 (9H, s), 2.08-2.16 (6H, m), 2.50-4.80(18H, m), 5.55-5.85 (2H, m), 6.60-6.80 (1H, m), 6.90-7.20 (2H, m),7.30-7.70 (2H, m), 8.13 (1H, br s)

[0727] MASS: 670 (M+H)⁺

EXAMPLE 45

[0728] A solution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(2E)-3-[(3R)-4-(tert-butoxycarbonyl)morpholin-3-yl]-2-propenyl]-2-(3,4-dimethylbenzyl)piperazine(1.36 g) in ethyl acetate (13 ml) was treated 4N hydrogen chloride inethyl acetate (3.12 ml) at room temperature for 18 hours and then at 40°C. for 5 hours. The solution was diluted with hexane and stirred for 1hour. The resulting precipitate was collected by filtration and driedunder reduced pressure to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(2E)-3-[(3R)-3-mprpholinyl]-2-propenyl]-piperazinedihydrochloride (1.11 g) as a white powder.

[0729] mp: 225-232° C.

[0730] [α]_(D) ²⁵: −12.00° (C=0.50, MeOH)

[0731] IR (KBr): 1645 cm⁻¹

[0732] NMR (DMSO-d₆, δ): 2.10-2.18 (6H, m), 2.70-5.10 (18H, m),5.80-6.25 (2H, m), 6.60-6.70 (1H, m), 6.90-7.20 (2H, m), 7.39-7.69 (2H,m), 8.15-8.20 (1H, m), 9.60-10.0 (2H, m)

[0733] MASS: 570 (M+H)⁺ (free)

[0734] Elemental Analysis Calcd. for C₂₉H₃₃F₆N₃O₂.2HCl.1.0H₂O: C 52.73,H 5.65, N 6.36 Found: C 52.65, H 5.76, N 6.26

EXAMPLE 46

[0735] To a solution of(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-pyrazolylmethyl)-piperazine(500 mg) and tert-butyl brornoacetaze (225 mg) in N,N-dimethylformamide(7.5 ml) was added potassium carbonate (390 mg), and the mixture wasstirred at 60° C. for 7 hours. Water was added to the mixture and theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with brine, dried over magnesiuw sulfate, evaporated underreduced pressure, and purified by column chromatography on a silica gelusing a mixture of ethyl acetate and hexane (1:1) as eluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[[1-(tert-butoxycarbonylmethyl)-1H-pyrazol-4-yl]methyl]-2-(3,4-dimethylbenzyl)piperazineas an oil.

[0736] NMR (DMSO-d₆, δ): 1.01 (9H, s), 2.05-2.15 (6H, s), 2.52-4.90(11H, m), 4.90 (2H, s), 6.53-6.58 (1H, m), 6.90-7.00 (2H, m), 7.41 (2H,s), 7.65 (2H, s), 8.13 (1H, br s)

[0737] MASS: 639 (M+H)⁺

EXAMPLE 47

[0738] A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[[1-(tert-butoxycarbonylmethyl)-1H-pyrazol-4-yl]methyl]-2-(3,4-dimethylbenzyl)piperazine(425 mg) in dichiloromethane (2.5 ml) was treated with trifluoroaceticacid (2.5 ml) at room temperature for 1 hour. The mixture was adjustedto pH 7.4 with aqueous sodium bicarbonate solution and evaporated underreduced pressure. The residue was washed with a mixture ofdichloromethane and methanol (9:1), and the solution was evaporatedunder reduced pressure and purified by column chromatography on a silicagel using a mixture of methanol and chloroform (1:9) as eluent andsubsequent crystallization from ethyl acetate, isopropyl ether, andhexane to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4,-[[1-(carboxymethyl)-1H-pyrazol-4-yl]methyl]-2-(3,4-dimethylbenzyl)piperazine (395 mg) as a white powder.

[0739] mp: 223-230° C.

[0740] [α]_(D) ²⁵: −15.10° (C=0.50, MeOH)

[0741] IR (KBr): 1683, 1604 cm⁻¹

[0742] NMR (DMSO-d₆, δ): 2.06-2.15 (6H, m), 2.52-4.90 (11H, m), 4.54(2H, s), 6.50-6.60 (1H, m), 6.90-7.00 (2H, m), 7.31 (1H, s), 7.40 (1H,s), 7.57-7.64 (2H, m), 8.14 (1H, s)

EXAMPLE 48

[0743] To a solution of(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl-]-4-[[1-(carboxymethyl)-1H-pyrazol-4-yl]methyl]-2-(3,4-dimethylbenzyl)piperazine(120 mg) in tetrahydrofuran (1 ml) were added 1-hydroxybenzotriazolehydrate (176 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (240 mg) and morpholine (0.11 ml, at room temperature, andthe mixture was stirred at rcom temperature overnight. The mixture wasquenched with water, and extracted with ethyl acetate. The organic layerwas washed with brine, dried over magnesium sulfate, and evaporatedunder reduced pressure. The residue was purified by columnchromatography on a silica gel using a mixture or methanol anc ethylacetate (1:9) as eluent to give a crude oil (76.7 mg) . The oil wasdissolved in ethyl acetate (0.7 ml) and added 4N hydrogen chloride inethyl acetate (0.15 ml) at room temperature. After the addition ofisopropyl ether, the resulting precipitate was filtered off and driedunder reduced pressure to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[[1-(morpholinocarboxymethyl)-1H-pyrazol-4-yl]methyl]piperazinehydrochloride (40 mg) as a powder.

[0744] mp: 120-130° C.

[0745] [α]_(D) ²⁵: −19.40° (C=0.25, MeOH)

[0746] IR (KBr): 1649 cm⁻¹

[0747] NMR (DMSO-d₆, δ): 2.06-2.16 (6H, s), 2.52-5.00 (19H, m), 5.19(2H, s), 6.55-6.62 (1H, m), 6.92-7.03 (2H, m) ) 7.44 (1H, s), 7.66-7.68(2H, m), 7.92 (1H, br s), 8.19 (1H, br s)

[0748] MASS: 652 (M+H)⁺ (free)

[0749] Elemental Analysis Calcd. for C₂₂H₃₅F₆N₅O₃.HCl.2.6H₂O: C 52.30, H5.65, N 9.53 Found, C 52.38, 5.63, N 9.22

EXAMPLE 49

[0750] The following compound was obtained according to a similar mannerto that of Example 34.

[0751](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3S)-3-(2-methylpropyl)morpholino-2-butynyl]piperazinedihydrochloride

[0752] mp: 125-138° C.

[0753] [α]_(D) ²⁵: +13.90° (C=0.50, MeOH)

[0754] IR (KBr): 1645 cm⁻¹

[0755] NMR (DMSO-d₆, δ): 0.80-1.80 (9H, m), 2.09-2.18 (6H, m), 2.83-5.13(20H, m), 6.60-6.70 (1H, m), 6.96-7.14 (2H, m), 7.6 (1H, br s), 7.67(1H, br s), 8.16 (1H, hr s)

[0756] MASS: 638 (M+H)⁺ (free)

[0757] Elemental Analysis Calcd. for C₃₄H₄₃Cl₂F₆N₃O₂.1.1H₂O: C 55.91, H6.24, N 5.75 Found: C 56.24, H 6.75, N 5.74

EXAMPLE 50

[0758] The following compoand was obtained accordirg to a similar mannerto that of Example 31.

[0759](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(7-oxa-4-azaspiro[2.5]octan-4-yl]-2-butynyl]piperazinedihydrochloride

[0760] [α]_(D) ^(27.9): −9.70° (C=0.50, MeOH)

[0761] IR (KBr): 3700-3000, 2700-2200, 1645, 1534, 1463, 1280, 1184 cm⁻¹

[0762] NMR (DMSO-d₆, δ): 0.90-1.00 (4H, m), 3.00-4.70 (19H, m),6.60-8.20 (6H, m)

[0763] MASS: 608 (M+H)⁺ (free)

[0764] Elemental Analysis Calcd. for C₃₂H₃₅F₆N₃O₂.2HCl.2H₂O: C 53.64, H5.77, N 5.86 Found: C 53.92, H 6.05, N 5.61

EXAMPLE 51

[0765] The following compounds were obtained according to a similarmanner to that of Example 1-(1).

[0766] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[3-(4-methoxypyridin-3-yl)-2-propynyl]-piperazine

[0767] NMR (CDCl₃, δ): 2.00-5.20 (11H, m), 3.92 (3H, s), 6.80-8.00 (11H,mn), 8.30 (1H, br s)

[0768] MASS: 601 (M+H)⁺ (free)

[0769] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(4-methoxypyridin-3-yl)-2-propynyl]piperazine

[0770] NMR (CDCl₃, δ): 2.00-5.20 (17H, m), 3.93 (3H, s), 6.60-8.80 (9H,m), 8.02 (1H, s), 8.30-8.50 (1H, m)

[0771] MASS: 590 (M+H)⁺

EXAMPLE 52

[0772] The following compounds were obtained according to a similarmanner to that of Example 5-(2).

[0773] (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2- (1H-indol-3-yl)methyl]-4-3-(4-methoxypyridin-3-yl)-2-propynyl]-piperazinedihydrochloride

[0774] mp: 162-167° C.

[0775] [α]_(D) ^(26.6): +4.90° (C=0.50, MeOH)

[0776] IR (KBr): 3700-3300, 2700-23001 1641, 1502, 1430, 1363, 1280 cm⁻¹

[0777] NMR (DMSO-d₆, δ): 3.00-5.20 (14H, m), 6.60-8.30 (9H, m),8.80-9.90 (2H, m), 10.96 (H, br s)

[0778] MASS: 601 (M+H)⁺ (free)

[0779] Elemental Analysis Calcd. for C₃₁H₂₆F₆N₄O₂.2HCl.2.2H₂O: C 52.16,H 4.91, N 8.32 Found: C 52.21, H 4.58, N 7.86

[0780] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(4-methoxypyridin-3-yl)-2-propynylpiperazine dihydrochloride

[0781] mp: 150-153° C.

[0782] [α]_(D) ^(24.9): −7.45° (C=0.55, MeOH)

[0783] IR (KBr): 3600-3300, 2700-2200, 1639, 1500, 1430, 1317, 1280 cm⁻¹

[0784] NMR (DMSO-d₆, δ): 2.00-2.20 (6H, m), 2.80-5.20 (11H, m),6.60-7.80 (6H, m), 8.20 (1H, br s), 8.81-8.97 (2H, m)

[0785] MASS: 590 (M+H)⁺ (free)

[0786] Elemental Analysis Calcd. for C₃₁H₂₉F₆N₃O₂.2HCl.2.2H₂O: C 52.97,H 5.27, N 5.93 Found: C 53.03, H 5.08, N 5.98

EXAMPLE 53

[0787] The following compounds were obtained according to a similarmanner to that of Example 3.

[0788] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[-3-(4-methoxypyridin-3-yl)propyl]piperazinedihydrochloride

[0789] mp: 165-170° C.

[0790] [α]_(D) ^(24.9): −1.91° (C=0.55, MeOH)

[0791] IR (KBr): 3700-2300, 1643, 1502, 1432, 1363, 1280, 1222 cm⁻¹

[0792] NMR (DMSO-d₆, δ): 2.00-2.30 (2H, m), 2.60-5.20 (16H, m),6.60-8.30 (9H, m), 8.70-8.90 (2H, m), 10.95 (1H, br s), 11.60-11.80 (2H,m)

[0793] MASS: 605 (M+H)⁺ (free)

[0794] Elemental Analysis Calcd. for C₃₁H₃₀F₆N₄O₂.2HCl.2.8H₂O: C 51.15,H 5.21, N 7.70 Found: C 51.11, H 5.40, N 7.61

[0795] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(4-methoxypyridin-3-yl)propyl]-piperazinedihydrochloride

[0796] mp: 159-168° C.

[0797] [α]_(D) ^(26.9): −10.91° (C=0.55, MeOH)

[0798] IR (KBr): 3600-3300, 2700-2300, 1643, 1502, 1430, 1361, 1280 cm⁻¹

[0799] NMR (DMSO-d₆, δ): 2.00-5.20 (21H, m), 4.13 (3H, s), 6.60-7.80(6H, m), 8.20-8.30 (1H, m), 8.70-8.90 (2H, m), 11.60-11.90 (2H, m)

[0800] MASS: 594 (M+H)⁺ (free)

[0801] Elemental Analysis Calcd. for C₃₁H₃₃F₆N₃O₂.2HCl.2.4H₂O: C 52.50,H 5.97, N 5.60 Found: 52.46, H 5.65, N 5.92

EXAMPLE 54

[0802] A solution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[3-[6-(tert-butoxycarbonylamino)-pyridin-3-yl]-2-propynyl]piperazine(127 mg) prepared by a similar manner to that of Example 5-(1) andtrifluoroacetic acid (5 ml) in dichloromethane (5 ml) was stirred atroom temperature for 2 hours. The reaction mixture was concentratedunder reduced pressure and the residue was partitioned between saturatedaaueous sodium bicarbonate solution. The organic layer was separated,dried over magnesium sulfate and concentrated under reduced pressure.The syrup obtained was dissolved into ethyl acetate and treated with 4Nhydrogen chloride in ethyl acetate to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)-methyl]-4-[3- (6-aminopyridin-3-yl)-2-propynyl]piperazine dihydrochaloride (80mg).

[0803] mp: 190-195° C.

[0804] [α]_(D) ^(24.0): −13.47° (C=0.23, MeOH)

[0805] IR (KBr): 3600-3000, 2700-2500, 1668, 1619, 1428, 1359, 1280 cm³¹¹

[0806] NMR (DMSO-d₆, δ): 3.00-5.20 (11H, m), 6.60-7.50 (6H, m),7.70-8.30 (5H, m), 8.20-8.50 (2H, m), 11.95-11.10 (1H, br s)

[0807] MASS: 586 (M+H)⁺ (free)

[0808] Elemental Analysis Calcd. for C₃₀H₂₅F₆N₅O.2HCl.2.5H₂O: C 51.22, H4.58, N 9.95 Found: C 51.17, H 4.40, N 9.27

EXAMPLE 55

[0809] The following compound was obtained according to a similar mannerto that of Example 54.

[0810](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(6-aminopyridin-3-yl)-2-propynyl]-piperazine dihydrochloride

[0811] mp: 183-189° C.

[0812] IR (KBr): 3600-2500, 1644, 1596, 1525, 1375, 1280 cm⁻¹

[0813] NMR (DISO-d₆, δ): 2.00-2.25 (6H, m), 2.80-5.25 (13H, m),6.60-8.40 (9H, m), 8.00-8.80 (2H, m)

[0814] MASS: 575 (M+H)⁺ (free)

[0815] Elemental Analysis Calcd. for C₃₀H₂₈F₆N₄O.2HCl.1.5H₂O: C 53.42, H4.93, N 8.31 Found: C 53.08, H, 5.01, N 8.12

EXAMPLE 56

[0816] The following compounds were obtained according to a similarmanner to that of Example 5.

[0817] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[3-(2-pyridyl)-2-prooynylipiperazine

[0818] IR (KBr): 3700-3200, 1640, 1278, 1136 cm⁻¹

[0819] NMR (DMSO-d₆, δ): 2.20-4.00 (9H, m), 4.30-5.20 (2H, m), 7.00-8.65(14H, m)

[0820] MASS: 582 (M+H)⁺, 467

[0821] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl)methyl]-4-[(2E)-3-(3-pyridyl)-2-propenyl]piperazinedihydrochloride

[0822] mp: 195-203° C.

[0823] [α]_(D) ^(24.9): −11.20° (C=0.50, MeOH)

[0824] IR (KBr): 3600-3300, 2700-2500, 1644, 1430, 1363, 1280, 1184 cm⁻¹

[0825] NMR (DMSO-d₆, δ): 3.00-5.20 (11H, m), 6.60-7.60 (6H, m),7.70-9.00 (8H, m), 11.00 (1H, br s), 12.00-12.40 (2H, m)

[0826] MASS: 773 (M+H)⁺ (free)

[0827] Elemental Analysis Calcd. for C₃₀H₂₆F₆N₄O.2HCl.2.5H₂O: C 52.18, H4.82, N 8.11 Found: C 51.94, H 4.77, N 7.77

[0828] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(2Z)-3-(3-pyridyl)-2-propenyl]-piperazinedihydrochloride

[0829] mp: 170-174° C.

[0830] [α]_(D) ^(23.0): −7.30° C. (C=0.50, MEeOH) IR (KBr): 3600-3300,2700-2500, 1644, 1550, 1430, 1363, 1280 cm⁻¹

[0831] NMR (DMSO-d₆, δ): 2.00-2.30 (6H, m), 2.80-5.20 (11H, m),6.40-8.40 (10H, m) 8.70-8.85 (2H, m), 12.00-12.20 (2H, m)

[0832] MASS: 562 (M+H)⁺ (free)

[0833] Elemental Analysis Calcd. for C₃₀H₂₉F₆N₃O.2HCl.2.5H₂O: C 53.03, H5.34, N 6.18 Found: C 52.99, H 5.41, N 5.91

[0834] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[4-(2-pyridyl)-3-butynyl]piperazine

[0835] NMR (CDCl₃, δ): 1.80-5.20 (13H, m), 6.80-8.00 (12H, m), 8.19 (1H,s), 8.55 (1H, d, J=4.0Hz)

[0836] MASS: 585 (M+H)⁺

EXAMPLE 57

[0837] The following compounds were obtained according to a similarmanner to that of Example 5.

[0838] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(6-methoxypyridin-3-yl)propyl]-piperazinedihydrochloride

[0839] mp:127-137° C.

[0840] [α]_(D) ^(22.5): −15.93° (C=0.16, MeOH)

[0841] IR (KBr): 3600-3300, 2700-2500, 1646, 1556, 1434, 1280, 1184 cm⁻¹

[0842] NMR (DMSO-d₆, δ):1.90-5.20 (21H, m), 3.84 (3H, s), 6.60-7.30 (4H,m), 7.40-7.80 (3H, m), 8.00-8.30 (2H, m)

[0843] MASS: 594 (M+H)⁺ (free)

[0844] Elemental Analysis Calcd. for C₃₁H₃₃F₆N₃O₂.2HCl.1.2H₂O: C 54.11,H 5.48, N 6.11 Found: C 54.09, H 5.75, N 5.83

[0845] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[3-(6-methoxypyridin-3-yl)propyl]piperazinedihydrochloride

[0846] mp: 195-200° C.

[0847] [α]^(22.6): −2.03° (C=0.32, MeOH)

[0848] IR (KBr): 3600-3300, 2700-2300, 1644, 1556, 1494, 1432, 1363,1280, 1180 cm⁻¹

[0849] NMR (DMSO-d₆, δ): 2.20-5.20 (15H, m), 3.79 (3H, s), 6.60-8.30(11H, m), 10. 95 (1H, br s), 11.60-11.80 (2H, m)

[0850] MASS: 605 (M+H)⁺ (Free)

[0851] Elemental Analysis Calcd. for C₃₁H₃₀F₆N₄O₂.2HCl.1.5H₂O: C 52.58,H 5.01, N 7.95 Found: C 52.89, H 5.40, N 7.63

[0852] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[3-(2-pyridyl)propyl]piperazinedihydrochloride

[0853] [α]_(D) ^(26.8): −27.60° (C=0.50, MeOH)

[0854] IR (KBr): 3700-3000, 2700-2200, 1647, 1279, 1136 cm⁻¹

[0855] NMR (DMSO-d₆, δ): 2.20-4.30 (13H, m), 4.40-5.40 (2H, m),7.00-8.90 (14H, m)

[0856] MASS: 586 (M+H)⁺ (free)

[0857] Elemental Analysis Calcd. for C₃₂H₂₉F₆N₃O.2HCl.2.5H₂O: C 54.63, H5.16, N 5.97 Found: C 54.55, H 5.37, N 5.56

[0858] (4)(2R)-1-[3,5-Bis(trifluoromethyi)benzoyl]-2-[(1H-indol-3-yl)methyll-4-[4-(2-pyridyl)butyl]piperazinedihydrochioride

[0859] mp: 155-160° C.

[0860] [α]_(D) ^(27.0):+9.50° (C=0.10, MeOH)

[0861] IR (KBr): 3700-3000, 2700-2200, 1641, 1459, 1428, 1280, 1137 cm⁻¹

[0862] NMR (DMSO-d₆, δ): 1.70-2.20 (4H, m), 2.60-5.20 (13H, m),6.60-8.80 (12H, m), 11.00 (1H, br s), 11.40-1180 (2H, m)

[0863] MASS: 589 (M+H)⁺ (free)

[0864] Elemental Analysis Calcd. for C₃₁H₃₀F₆N₄O.2HCl.2.0H₂O: C 53.38, H5.20, N 8.03 Found: C 53.34, H 5.38, N 7.78

EXAMPLE 58

[0865] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]piperazine(0.83 g), methyl α-bromophenylacetate (0.42 g), potassium carbonate (1.0g) in N,N-dimethylformamide (5 ml) was stirred at 50° C. for 3 hours.The reaction mixture was poured into water and the resultingprecipitates were collected by filtration. The precipitates werepurified by column chromatography on silica gel using a mixture ofdichloromethane and ethyl acetate as eluent to give a mixture ofdiastereoisomers, methyl(2R,2S)-2-[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]piperazin-4-yl]-2-phenylacetate(1.00 g).

[0866] NMR (CDCl₃, δ): 2.00-5.20 (4H, m), 3.69 (3H, s), 6.70-8.20 (14H,m)

[0867] MASS: 604 (M+H)⁺ (free)

EXAMPLE 59

[0868] A solution of the mixture of diastereoisomers, methyl(2R,2S)-2-[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]piperazin-4-yl]-2-phenylacetate(360 mg) and 1N sodium hydroxide (1.5 ml) in methanol (5 ml) was stirredat 50° C. for 2 hours. The mixture was concentrated under reducedpressure until aqueous solutlon. The solution was diluted with water andthe solution was made acidic (about pH 5) with diluted hydrochloric acidand extracted with ethyl acetate. The organic layer was dried overmagnesium sulfate and concentrated under reduced pressure to give amixture of diastereoisomers,(2R,2S)-2-[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-piperazin-4-yl]-2-phenylaceticacid (0.33 g).

[0869] NMR (CDCl₃, δ): 2.20-5.80 (10H, m), 6.60-8.20 (14H, m)

[0870] MASS: 590 (M+H)⁺ (free)

EXAMPLE 60

[0871] Isobutyl chloroformate (0.116 ml) was added dropwise to asuspension of the mixture of ciastereoisomers,(2R,2S)-2-[(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)-methyl]piperazin-4-yl]-2-phenylaceticacid (0.5 g) and N-methylmorpholine (0.103 ml) in 1,2-dimethoxyethane (3ml) under −18° C. After being stirred at the same temperature for 30minutes, a solution of sodium borohydride (32 mg) in water (0.5 ml) wasadded to the mixture all at once. After being stirred at roomtemperature for 30 minutes, 1N sodium hydroxide solution was added tothe mixture and the whole was stirred at room temperature for 1 hour.The mixture was neutralized with diluted hydrochloric acid, andextracted with ethyl acetate. The extract was dried over magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel using a mixed eluent ofdichloromethane and methanol. The fractions containing the objectivecompound were collected and evaporated under reduced pressure to give amixture of diastereoisomers,(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[(1R,1S)-1-phenyl-2-hydroxyethyl]-piperazine(0.42 g).

[0872] NMR (CDCl₃, δ): 1.90-5.20 (13H, m), 6.60-8.20 (14H, m)

[0873] MASS: 576 (M+H)⁺

EXAMPLE 61

[0874] Methanesulfonyl chloride (0.058 ml) was added to a solution ofthe mixture of diastereoisomers,(2R)-1-(3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[(1R,1S)-1-phenyl-2-hydroxyethyl]piperazine(0.36 g) and triethylamine (0.16 ml) in dichloromethane (10 ml) under−18° C. After being stirred at the same temperature for 30 minutes,additional methanesulfonyl chloride (0.058 ml) and triethylamine (0.16ml) were added to the mixture. After being stirred at the sametemperature for further 30 minutes, the reaction mixture was washed withwater, dried over magnesium sulfate and evaporated under reducedpressure to give the corresponding mesylate. A mixture of the mesylateand morpholine (0.4 ml) in 1,4-dioxane was stirred at 50° for 3 hours.The reaction mixture was concentrated under reduced pressure to give asyrup, which was partitioned between water and ethyl acetate. Theorganic layer was separated, washed with brine, dried over magnesiumsulfate and concentrated under reduced pressure to give the crudemixture of diastereoisomers, which was purified by column chromatographyon silica gel using a mixed eluent of dichloromethane and methanol. Thefaster eluting fractions were collected, evaporated under reducedpressure and treated with 4N hydrogen chloride in ethyl acetate to givea diastereoisomer of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[(1Ror 1S)-1-phenyl-2-morpholinoethyl]-piperazine dihydrochloride.

[0875] mp: 203-207° C.

[0876] [α]_(D) ^(21.7): −6.0° (C=0.25, MeOH)

[0877] IR (KBr): 3700-3300, 3100-2200, 1641, 1450, 1432, 1363, 1280 cm⁻¹

[0878] NMR (DMSO-d₆, δ): 2.40-5.20 (20H, m), 6.60-8.30 (8H, m), 10.9(1H, s)

[0879] MASS: 644 (M+H)⁺ (free)

[0880] Elemental Analysis Calcd. for C₃₄H₃₄F₆N₄O₂.2HCl.2/3H₂O: C 55.97,H 5.16, N 7.68 Found: C 55.98, H 5.48, N 7.26

[0881] The slower eluting fractions were collected, evaporated underreduced pressure and treated with 4N hydrogen chloride in ethyl acetateto give a diastereoisomier of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[(1Sor 1R)-1-phenyl-2-morpholinoethyl]piperazine dihydrochloride.

[0882] mp: 207-212° C.

[0883] IR (KBr): 3700-3200, 3000-2300, 1643, 1450, 1432, 1280, 1182 cm⁻¹

[0884] NMR (DMSO-d₆, δ): 2.40-5.20 (20H, m), 6.55-8.35 (8H, m), 10.95(1H, s), 11.00-12.10 (2H, m)

[0885] MASS: 644 (M+H)⁺ (free)

[0886] Elemental Analysis Calcd. for C₃₄ ₃₄F₆N₄O₂.2HCl.0.5H₂O: C 56.20,H 5.13, N 7.71 Found: C 56.15, H 5.52, N 7.32

EXAMPLE 62

[0887] The following compound was obtained according to a similar mannerto that of Example 45.

[0888] (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-[(2R,2S)-2-morpholinyl]-2-propenyl]-piperazinedihydrochloride

[0889] mp: 1:60-163° C.

[0890] [α]_(D) ²⁵: −12.50° (C=0.50, MeOH)

[0891] IR (KBr): 1645 cm ⁻¹

[0892] NMR (DMSO-d₆, δ): 2.08-2.18 (6H, m), 2.55-5.10 (18H, m), 580-6.20(2H, m), 6.60-6.70 (1H, m), 6.90-7.20 (2H, m), 7.47-7.70 (2H, m),8.15-8.20 (1H, m)

[0893] MASS: 570 (M+H)⁺ (free)

[0894] Elemental Analysis Calcd. for C₂₉H₃₅F₆N₃O₂.2HCl.1.0H₂O: C 52.59,H 5.65, N 6.34 Found: C 52.85, H 5.97, N 6.16

EXAMPLE 63

[0895] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine(500 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5 μl) intetrahydrofuran (2.5 ml) was cooled to −30° C. with stirring undernitrogen atmosphere. Acrolein (90%, 0.225 ml) was added to the mixturewhile maintaining the temperature at −20˜40° C. for a period of 10minutes and then the resulting mixture was stirred at 0° C. After 6hours, the reaction mixture was diluted with water and extracted withethyl acetate. The extract was washed with brine and dried overmagnesium sulfate. After evaporation of the solvent under reducedpressure, the resulting residue was chromatographed on a silica gelusing a mixture of hexane and ethyl acetate as eluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-formylethyl)piperazine(332 mg) as an oil.

[0896] NMR (DMSO-d₆, δ): 1.60-4.90 (19H, m), 6.55-6.75 (1H, m),6.90-7.15 (2H, m), 7.30-7.75 (2H, m), 8.13 (1H, br s), 9.70 (1H, s)

[0897] MASS: 501 (M+H)⁺

EXAMPLE 64

[0898] To a stirred mixture of 4-amino-3,3-dimethylmorpholinedihydrochloride (122 mg) in dichloromethane (5 ml) was addedtriethylamine (61 mg) at ice bath temperature. A solution of(2R)-1-3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethyl-benzyl)-4-(2-formylethyl)piperazine (150 mg) indichloromethane (2 ml) was added and the resulting mixture was stirredat room temperature. After 30 minutes, the reaction mixture wasconcentrated under reduced pressure. The resulting residue waschroimatographed on a silica gel using a mixture or hexane and ethylacetate as eluent and the desired product was treated with 4N hydrogenchloride in ethyl acetate to give(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(3,3-dimethylmorpholinoimino)propyl]piperazinedihydrochloride (122 mg).

[0899] IR (KBr): 3425, 2700, 2625, 1645, 1430, 1280, 1180, 1135 cm⁻¹

[0900] NMR (DMSO-d₆, δ): 1.06-1.40 (6H, m), 2.00-2.40 (6H, m), 2.60-5.80(19H, m), 6.64-8.30 (6H, m), 10.00-12.18 (2H, m)

[0901] MASS:613 (M+H)⁺ (free)

[0902] Elemental Analysis Calcd. for C₃₁H₃₈F₆N₄O₂.2HCl.2H₂O: C 51.60, H6.15, N 7.76 Found: C 51.82, H 6.49, N 7.29

EXAMPLE 65

[0903] To a stirred mixture of 4-aminohomomorpholine dihydrochloride(100 mg) in dichloromethane (5 ml) was added triethylamine (107 mg) atice bath temperature. A solution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-formylethyl)piperazine(200 mg) in dichloromethane (2 ml) was added and the resulting mixturewas stirred at room temperature. After 30 minutes, the reaction mixturewas concentrated under reduced pressure. The resulting residue waschromatograrhed on a silica gel using a mixture of hexane and ethylacetate as eluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(homomorpholinoimino)propyl]piperazine(110 mg) and an intermediate. This compound was dissolved in methanol (5ml) and sodium borohydride (17 mg) was added at ice bath temperature.After 2 hours, additional sodium borohydride (40 mg) was added and thereaction mixture was stirred at rooim temperature overnight. Thereaction mixture was diluted with water and then extracted withdichloromethane. The extract was washed with brine and dried overmagnesium sulfate. After evaporation of the solvent, the resultingresidue was purified by a silica gel column chromatography using amixture of dichloromethane and methanol (50:1) as eluent to give thedesired product, which was dissolved in ethyl acetate and treated with4N hydrogen chloride in ethyl acetate to afford(2R)-1-[3,5-bis-(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(homomorpholinoamino)propyl]piperazinedihydrochloride (66 mg)

[0904] [α]_(D) ²⁷: −13.7° (C=0.50, MeOH)

[0905] IR (KBr): 3450, 2700, 2620, 1645, 1430, 1280, 1185, 1135 cm⁻¹

[0906] MASS: 601 (M+H)⁺ (free)

[0907] Elemental Analysis Calcd. for C₃₀H₃₈F₆N₄O₂.2HCl.0.7H₂O: C 52.51,H 6.08, N 8.17 Found: C 52.51, H 6.05, N 7.86

PREPARATION 32

[0908] Di-tert-butyl dicarbonate (29.4 g) was added to a mixtuure of(2R)-2-(3,4-dimethylbenzyl)-4-benzylpiperazine dihydrochloride (45.0 g)and triethylamine (59.6 ml) In tetrahydrofuran (900 ml) underice-cooling. After 3 hours of stirring at the same temperature, stirringwas continued at room temperature for 9 hours. The mixture was pouredinto ice-water (1 l) and extracted with ethyl acetate (2.5 l). Theextract was washed successively with 1N hydrochloric acid and brine,dried over sodium sulfate and evaporated under reduced pressure to givea crude oil of(2R)-4-benzyl-1-tert-butoxycarbonyl-1-(3,4-dimethylbenzyl)piperazine(49.6 g).

[0909] NMR (CDCl₃, δ): 1.40 (9H, s), 1.90-2.06 (2H, m), 2.15-2.17 (6H,m), 2.60-4.4 (9H, m), 6.86-7.05 (3H, m), 7.20-7.39 (5H, m)

[0910] MASS (APCI): 395 (M+H)⁺, 339, 295

PREPARATION 33

[0911] A solution of(2R)-4-benzyl-1-tert-butoxycarbonyl-2-(3,4-dimethylbenzyl)piperazine(48.5 g) in methanol (730 ml) was hydrogenated over 20% palladiumhydroxide-carbon (0.3 g) at room temperture under atmospheric pressure.After removal of the catalyst by filtration, the filtrate was evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel using a mixed solvent of dichloromethaneand methanol (10:1). The fractions containing the objective compound wascollected and evaporated under reduced pressure to give an oil of(2R)-1-tert-butoxycarbonyl-2-(3,4-dimethylbenzyl)riperazine (33.7 g).

[0912] NMR (DMSO-d₆, δ): 1.26 (9H, s), 2.15-2.17 (6H, m), 2.30-4.05(10H, m), 6.86-7.05 (3H, m)

[0913] MASS (APCI): 305 (M+H)⁺, 249, 205

PREPARATION 34

[0914] A mixture of(2R)-1-tert-butoxycarbonyl-2-(3,4-dimethylbenzyl)piperazine (29.0 g)3,3-dimethyl-4-(4-chloro-2-butynyl)morpholinine hydrochloride (22.7 g),potassium carbonate (39.5 g) and potassium iodide (1.58 g) inN,N-dimethylformamide (145 ml) was stirred at room temperature for 2hours, followed by 53° C. for 3 hours. After being cooled to roomtemperature, the mixture was poured into ice-water (1.2 l) and extractedwith ethyl acetate (1.2 l). The extract was washed with water (1 l), andre-extracted with 1N hydrochlioric acid (190 ml). The acidic aqueouslayer was separated and the pH of the solution was made to 10 with 1Nsodium hydroxide. The alkaline solution was extracted with ethyl acetate(1.1 l) and the extract was washed with brine, dried over sodiumsulfate, and evaporated under reduced pressure to give an oil of(2R)-1-tert-butoxycarbonyl-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine(43.1 g).

[0915] NMR (DMSO-d₆, δ): 0.95 (6H, s), 1.26 (9H, s), 2.03-4.20 (25H, m),6.80-7.05 (3H, m)

[0916] MASS (APCI): 470 (M+H)⁺

PREPARATION 35

[0917] A solution of 4N hydrogen chloride in ethyl acetate was added toa solution of(2R)-1-tert-butoxycarbonyl-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine(40.0 g) in ethanol (120 ml) at room temperature and the whole wasstirred for 12 hours. The reaction mixture was concentrated underreduced pressure and the residue was partitioned between ethyl acetate(500 ml) and potassium carbonate solution. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (300ml). The combined extract was dried over sodium sulfate and evaporatedunder reduced pressure, and the residue was purified by columnchromatographv on silica gel using a mixed solvent of n-hexane and ethylacetate (3:1). The fractions containing the objective compound werecollected and evaporated under reduced pressure, and treated with 4Nhydrogen chloride in ethyl acetate to give(3R)-3-(3,4-dimethylbenzyl)-1-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazinetrihydrochloride (37.7 g)

[0918] mp: 264-272° C.

[0919] [α]_(D) ²⁷: −23.6° (C=0.50 MeOH)

[0920] IR (KBr): 3500-3400, 2900, 2570, 2480, 1637, 1626, 1508, 1455,1180 cm⁻¹

[0921] NMR (DMSO-d₆, δ): 1.33 (3H, s), 1.39 (3H, s), 2.21 (6H, s),2.80-4.60 (20H, m), 6.90-7.20 (3H, m), 9.90-10.40 (3H, m)

[0922] MASS (APCI): 370 (M+H)⁺ (free)

PREPARATION 36

[0923] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.22 ml) was addedover 5 minutes to a mixture of(3R)-3-(3,4-dimethylbenzyl)-1-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazinetrihydrochloride (0.48 g) and 3,5-bis(trifluoromethyl)benzoic acid (0.27g), 1-hydroxybenzotriazole (0.15 g) and triethylamine (0.35 ml) indichloromethane (10 ml). After 2 hours of stirring at room temperature,the reaction mixture was directly purified by column chromatography onsilica gel using a mixed solvent of dichloromethane and methanol (40:1).The fractions containing the objective compound was collected andevaporated under reduced pressure. The residue was treated with 4Nhydrogen chloride in ethyl acetate and recrystallized from a mixture ofacetone and water to give colorless crystals of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazinedihydrochloride (525 g).

[0924] mp: 180-190° C.

[0925] [α]_(D) ^(28.3): −7.24° (C=1.05, MeOH)

[0926] IR (Nujol): 3300, 2700-2400, 1635 cm¹

[0927] NMR (DMSO-d₆, δ): 1.30-1.40 (6H, m), 2.00-5.22 (25H, m),6.60-8.20 (6H, m), 12.05-12.20 (2H, m)

[0928] MASS (APCI): 610 (M+1H) (free)

[0929] Elemental Analysis Calcd. for C₃₂H₃₇F₆N₃O₂.2HCl.2.5H₂O: C 52.82,H 6.09, N 5.68 Found: C 52.84, H 5.89, N 5.78

PREPARATION 37

[0930] 3,3-Dimethylmorpholine hydrochloride (5.3 g) was added by smallportions over 1 hour to a mixture of 1,4-dichloro-2-butyne (6.9 ml) andpotassium carbonate (9.8 a) in N,N-dimethylformamide (100 ml). After 20hours of stirring, the mixture was poured into ice-water (200 ml) andextracted with isopropyl ether (100 ml) two times. The extract waswashed with brine (100 ml), dried over magnesium sulfate, and evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel using a mixed solvent of n-hexane and ethylacetate (4:1). The fractions containing the objective compound wascollected and evaporated under reduced pressure, and treated with 4Nhydrogen chloride in ethyl acetate to give brownish powders of3,3-dimethyl-4-(4-chloro-2-butynyl)morphlinine hydrochloride (5.32 g).

[0931] NMR (DMSO-d₆, δ): 1.35-1.39 (6H, m), 3.20-4.40 (8H, m), 4.56 (2H,s), 11.50-11.90 (1H, m)

[0932] MASS (APCI): 202 (M+H)⁺ (free), 204

PREPARATION 38

[0933] A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine(3.0 g), propargyl bromide (0.84 g) and potassium carbonate (1.17 g) inN,N-dimethylformamide (300 ml) was stirred at room temperature for 1.5hours. The mixture was poured into ice-water and extracted with ethylacetate. The extract was washed with brine, dried over magnesium sulfateand evaporated under reduced pressure to give a syrup of(2R)-1-[3,5-bis-(trifluoromethyl)benzoyl]-2-(3,4-dimezhylbenzyl)-4-(2-propynyl)piperazine(3.80 g).

[0934] NMR (DMSO-d₆, δ): 2.00-5.00 (18H, m), 6.66-8.20 (6H, m)

[0935] MASS (APCI): 483 (M+H)⁺

PREPARATION 38

[0936] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-propynyl)piperazine(0.49 g), 3,3-dimethylmorpholine hydrochloride (0.185 g),paraformaldehyde (62 mg), diisopropylethylamine (0.21 ml), and copper(1) iodide (20 mg) in 1,4-dioxane (5 ml) was stirred at 70° C. for 1.5hours. After removal of the solvent by evaporation, the residue waspurified by column chromatography on silica gel using a mixed solvent ofdichloromethane and methanol (40:1). The fractions containing theobjective compound was collected and evaporated under reduced pressureto give a syrup of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine(0.45 g).

[0937] NMR (CDCl₃, δ): 0.97 (6H, s), 2.03-5.00 (25H, m), 6.66-8.23 (6H,m)

[0938] MASS (APCI): 610 (M+H)⁺, 513 its hydrochloride

[0939] mp: 185-188° C.

[0940] [α]_(D) ²⁸: −8.6° (C=0.18, MeOH)

[0941] IR (KBr): 2928, 2585, 25151 1633, 1433, 1279, 1180, 1132 cm⁻¹

[0942] NMR (DMSO-d₆ , δ): 1.33-1.40 (6H, m), 2.09-2.18 (6H, m),2.50-5.20 (19H, m), 6.66-8.15 (6H, m)

[0943] MASS (APCI): 610 (M+H)⁺ (free)

PREPARATION 40

[0944] A mixture of 37% aqueous formaldehyde (0.21 g),(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-piperazine(0.75 g), propargyl alcohol (0.11 ml), copper(II) sulfate pentahydrate(1.3 mg) and potassium iodide (2.8 mg) in 1,4-dioxane was stirred at100° C. for 2 hours. After being cooled to room temperature, the mixturewas made basic with aqueous saturated sodium hydrogen carbonatesolution. The resulting mixture was filtered and the filtrate wasextracted with ethyl acetate. The extract was washed with brine, driedover magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel using amixed solvent of n-hexane and ethyl acetate (4:1). The fractionscontaining the objective compound was collected and evaporated underreduced pressure to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-hydroxy-2-butynyl)piperazine(0.78 g) as a syrup.

[0945] NMR (CDCl₃, δ): 1.99-5.00 (19H, m), 5.15 (1H, t, J=5.9Hz),6.66-8.23 (6H, m)

[0946] MASS (APCI): 513 (M+H)⁺, 499, 483

PREPARATION 41

[0947] The following compound was obtained according to a similar mannerto that of Example 39.

[0948](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine

[0949] NNR (CDCl₃, δ): 0.97 (6H, s), 2.03-5.00 (25H, m), 6.66-8.23 (6H,m)

[0950] MASS (APCI): 610 (M+H)⁺, 513

PREPARATION 42

[0951] A mixture of 3,3-dimethylmorpholine hydrochloride (30.0 g),propargyl bromide (16.4 ml) and potassium carbonate (63 g) inN,N-dimethylformamide (300 ml) was stirred at 45-48° C. for 1.5 hours.After being cooled to room temperature, the mixture was poured intoice-water (800 ml) and extracted with ethyl acetate (500 ml) two times.The extract was washed with brine (400 ml), dried over magnesium sulfateand filtered. The filtrate was treated with 4N hydrogen chloride inethyl acetate (98 ml) under ice-cooling. The solution was concentratedunder reduced pressure to give a crude solid, which was collected byfiltration and washed with isopropyl ether to give brownish crystals of3,3-dimethyl-4-(2-propynyl)morpholine hydrochloride (35 g).

[0952] IR (KBr): 3500-3400, 2900, 2570, 2480, 1637, 1626, 1508, 1455,1180 cm⁻¹

[0953] NMR (DMSO-d₆, δ): 1.20-1.50 (6H, m), 3.20-4.20 (9H, m), 11.91(1H, s)

[0954] MASS (APCI): 154 (M+H)⁺ (free)

PREPARATION 43

[0955] A mixture of 3,3-dimethyl-4-(2-propyryl)morpholine hydrochloride(0.24 g), 37% aqueous formaldehyde (0.16 ml),(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine(0.57 g), copper(II) sulfate pentahydrate (5 mg) and potassium iodide(20 mg) in 1,4-dioxane (0.7 ml) was stirred at 90° C. for 1 hour. Afterbeing cooled to room temperature, the mixture was poured into ice-waterand the aqueous mixture was made alkaline with saturated aqueous sodiumhydrogen carbonate solution. The resulting mixture was extracted withethyl acetate. The extract was washed with brine, dried over magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel using a mixed solvent ofdichloromethane and methanol (40:1). The fractions containing theobjective compound was collected and evaporated under reduced pressureand treated with 4N hydrogen chloride in ethvi acetate solution. Theresulting mixture was evaporated under reduced pressure and the residuewas recrystallized from a mixture of acetone and water to give colorlesscrystals of(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazinedihydrochloride (0.64 g).

[0956] mp: 180-190° C.

[0957] [α]_(D) ^(28.3): −7.4° (C=1.05, MeOH)

[0958] IR (Nujol): 3300, 2700-2400, 1635 cm⁻¹

[0959] NMR (DMSO-d₆, δ): 1.30-1.40 (6H, m), 2.00-5.22 (25H, m),6.60-8.20 (6H, m), 12.05-12.20 (2H, m)

[0960] MASS (APCI): 610 (M+1H) (free)

[0961] Elemental Analysis Calcd. for C₃₂H₃₇F₆N₃O₂.2HCl.2.5H₂O: C 52.82,H 6.09, N 5.68 Found: C 52.84, H 5.89, N 5.78

PREPARATION 44

[0962] The following compounds were obtained according to a similarmanner to that of Preparation 1.

[0963] 1) 3-[2-(4-Methoxy)pyridyl]-2-propyn-1-ol

[0964] IR (KBr): 3130, 1598, 1562, 1471, 1425 cm⁻¹

[0965] NMR (DNSO-d₆, δ): 3.84 (3H, s), 4.31 (2H, d, J=6.0Hz), 5.41 (1H,t, J=6.0Hz), 6.97 (1H, dd, J=2.6, 5.8Hz), 7.06 (1H, d, J=2.6Hz), 8.35(1H, d, J=5.8Hz)

[0966] MASS (APCI): 164 (M+H)⁺134

[0967] (2) 3-[2-(4-Methoxycarbonyl)pyridyl]-2-propyn-1-ol

[0968] IR (KBr): 3133, 1598, 1568, 1430 cm⁻¹

[0969] NMR (DMSO-d₆, δ): 3.91 (3H, s), 4.35 (2H, d, J=6.0Hz), 5.75 (1H,d, J=6.0Hz), 7.70-7.80 (1H, m), 8.68 (1H, d, J=5.0Hz), 3.78 (1H, d,J=5.0Hz)

[0970] MASS (APCI): 192 (M+H)⁺

PREPARATION 45

[0971] (1) To a stirred solution of chioropyrazine (1.14 g) and[1,2-bis(diphenylphoschino)ethane]nickel(II) chloride (106 mg) in drytetrahydrofuran (40 ml) was added a solution of3,4-methylenedioxybenzylmagnesium chloride (0.6 M in tetrahydrofuran, 29ml) at 5° C. under nitrogen atmosphere over 1-5 minutes. After 1 hour ofstirring at 5° C., 3N hydrochloric acid was added slowly under nitrogenatmosphere and the mixture was stirred for 1 hour. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Thecombined extract was washed with water and dried over magnesium sulfate.The usual work up followed by flash chromatography on silica gel with amixture of n-hexane and ethyl acetate (10:1-4:1) gave2-(3,4-methylenedioxybenzy)pyrazine (454 mg) as a colorless oil.

[0972] NMR (CDCl₃, δ): 4-59 (2H, s,) 5.93 (2H, s), 6.75-6.88 (3H, m),8.44-8.56 (3, m)

[0973] MASS (APCI): 215 (M+H)⁺

[0974] (2) To a stirred solution of2-(3,4-methylenedioxybenzyl)-pyrazine (317 mg) in dry tetrahydrofuran(12 ml) was added a solution of diisobutylaluminum hydride (0.95 M inn-hexane, 15.6 ml) at 5° C. under nitrogen atmosphere. After 1 hour ofstirring at 5° C., the mixture was added saturated sodium sulfatesolution until gas evolution ceased. The insoluble materials wereremoved by filtration through Celite® and the organic layer wasseparated, dried over magnesium sulfate, and concentrated under reducedpressure. The residue was dissolved in ethyl acetate and treated with 4Nhydrogen chloride in ethyl acetate to give2-(3,4-methylenedioxy-benzyl)piperazine dihydrochloride (125 mg) as apowder.

[0975] NMR (DMSO-d₆, δ): 2.79-3-66 (9H, m), 6.02 (2H, s), 6.74-6.94 (3H,m), 9.79 (4H, br s)

[0976] MASS (APCI): 221 (M+H)⁺ (free)

PREPARATION 46

[0977] (1) To a stirred solution of 4-bromo-2-methylbenzoic acid (10.75g) in tetrahydrofuran (50 ml) was added boranetetrahydrofuran complex (1M in tetrahydrofuran, 150 ml) by syringe under nitrogen atmosphere at 5°C. and the mixture was heated under reflux for 18 hours. after cooling,water (50 ml) and potassium carbonate (20 g) were added to the solutionat 5° C. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The combined extract was washed withwater, dried over magnesium sulfate, and concentrated under reducedpressure to give 4-bromo-2-methylbenzyl alcohol (9.55 g). This compoundwas used to the next reaction without further purification.

[0978] (2) Tert-butylchlorodiphenylsilane (13.06 g) and imidazole (9.7g) were added to a solution of 4-bromo-2-methylbenzyl alcohol (9.55 g)in N,N-dimethylformamide (80 ml) at 5° C. and the mixture was allowed towarm to room temperature, and stirred for 18 hours. The mixture wasextracted with ethyl acetate and the extract was washed with water,dried over magnesium sulfate, and concentrated under reduced pressure togive 1-bromo-4-(tert-butyldiphenylsilyloxyrethyl)-3-methylbenzene (20.5g) as a colorless oil.

[0979] NMR (DMSO-d₆, δ): 1.03 (9H, s), 2.14 (3H, s), 4.70 (2H, s),7.34-7.71 (13H, m)

[0980] (3) To a stirred solution of1-bromo-4-(tert-butyldiphenylsilyloxymethyl)-3-methylbenzene (2.19 g) intetrahydrofuran (30 ml) was added 1.6 M butyllithium in hexane (4.69 ml)by syringe under nitrogen atmosphere at −78° C. After 30 minutes ofstirring at −78° C., N,N-dimethylformamide (1.16 ml) was added to thesolution at −78° C. and then the mixture was allowed to warm to 5° C.over 1.5 hours. Saturated ammonium chloride solution (10 ml) was addedto the mixture and the organic layer was separated, and the aqueouslayer was extracted with ethyl acetate. The combined extract was washedwith water, dried over magnesium sulfate, and concentrated under reducedpressure to give4-(tert-butyldiphenylsilyloxymethyl)-3-methylbenzaldehyde (1.90 g) as acolorless oil.

[0981] NMR (DMSO-d₆, δ): 1.06 9H, s), 2.20 (3H, s), 4.38 (2H, s),7.37-7.83 (13H, m), 9.97 (1H, s)

[0982] MASS (APCI): 389 (M+H)⁺

[0983] (4) To a stirred mixture of4-(tert-butyldiohenylsilyloxymethyl)-3-methylbenzaldehyde (1.94 g) and1,4-diacetyl-2,5-piperazinedione (991 mg) in a mixture ofN,N-dimethylformamide (10 ml) and tert-butanol (10 ml) was addedpotassium tert-butoxide (561 mg) at 5° C. The mixture was stirred for 1hour at room temperature and then poured into water (300 ml), andstirring was continued for 18 hours at room temperature. The resultingprecipitates were collected by filtration and washed with water andisopropyl ether, and dried under reduced pressure to give1-acetyl-3-(4-tert-butyldiphenylsilyloxymethyl-3-methylphenyl)methylene-2,5-piperazinedione (1.88 g) as a powder.

[0984] NMR (DMSO-d₆, δ): 1.05 (9H, s), 1.99 (3H, s), 2.19 (3H, s), 4.37(2H, s), 4.77 (2H, s), 6.93 (1H, s), 7.40-7.69 (13H, m), 10.37 (1H, s)

[0985] MASS (APC,): 527 (M+H)⁺

[0986] (5) A solution of1-acetyl-3-(4-tert-butyldiphenylsilyloxymethyl-3-methylphenyl)methylene-2,5-piperazinedione(6.3 g) in methanol (300 ml) was hydrogenated over 10% palladium-carbon(50% wet) for 4 hours at atmospheric pressure. After removal of thecatalyst by filtration, to the filtrate was added hydrazine monohydrate(721 mg). The mixture was stirred for 1 hour at room temperature andconcentrated under reduced pressure. The residue was triturated with amixture of isopropyl ether (200 ml) and n-hexane (400 ml) and theprecipitates were collected by filtration, and washed with isopropylether to give a crude product. This was purified by flash columnchromatography on silica gel usina ethyl acetate and a mixture ofdichloromethane and methanol (15:1) as eluent to give3-(4-tert-butyldiphenylsiyloxymethyl-3-methylbenzyl)-2,5-piperazinedione(4.67 g) as a powder.

[0987] NMR (DMSO-d₆, δ): 1.02 (9H, s), 2.12 (3H, s), 2.77-3.18 (3H, m),3.37 (1H, m), 4.04 (1, m), 4.72 (2H, s), 6.37-7.04 (2H, m), 7.29-7.66(1H, m), 7.94 (1H, m), 8.14 (1H, m)

[0988] MASS (APCI): 487 (M+H)⁺

[0989] (6) To a stirred solution of3-(4-tert-butyldiphenylsilyloxymethyl-3-methylbenzyl)-2,5-piperazinedione(1.46 g) in a mixture of tetrahydrofuran (40 ml) and 1,2-dimethoxyethane(40 ml) was added lithium aluminum hydride (683 mg) under nitrogenatmosphere at 5° C. and the mixture was heated under reflux for 6 hours.After cooling, the reaction mixture was quenched by sequential additionof water (1.5 ml), 15 sodium hydroxide solution 1.5 ml), and water (4.5ml). h insoluble materials were removed by filtration through Celite.The organic layer was dried over magnesium sulfate and concentratedunder reduced pressure to leave an oil which was purified by flashcolumn chromatograhy on silica gel using a mixture of dichloromethaneand methanol (50:1-90:1) to give1,4-bis(benzyloxycarbonyl)-2-(4-hydroxymethyl-3-methylbenzyl)piperazine(242 mg) as a powder.

[0990] NMR (DMSO-d₆, δ): 2.09 (3H, m), 2.58-3.22 (5H, m), 3.64-4.50 (6H,m), 4.82-5.21 (5H, m), 6.86-7.72 (13H, m)

[0991] (7) A solution of1,4-bis(benzyloxycarbonyl)-2-(4-hydroxymethyl-3-methylbenzyl)piperazine(6.3 g) in methanol (5 ml) was hydrogenated over 10% palladium-carbon(50% wet, 22 mg) for 6 hours at atmospheric pressure. After removal ofthe catalyst by filtration, the filtrate was treated with 4N hydrogenchloride in ethyl acetate and concentrated under reduced pressure togive 2-(4-hydroxymethyl-3-methylbenzyl)piperazine dihydrochloride (96mg) as a powder.

[0992] MASS (APCI): 221 (M+H)⁺ (free)

PREPARATION 47

[0993] (1) The following compound was obtained according to a similarmanner to that of Preparation 46-(4).

[0994] 1-Acetyl-3-[1,4-benzodioxan-6-yl)methylene]-2,5-piperazinedione

[0995] NMR (DMSO-d₆, δ): 2.48 (3H, s), 4.28 (4H, s), 4.35 (2H, s),6.86-7.16 (4H, m), 10.30 (1H, s)

[0996] MASS (APCI): 303 (M+H)⁺

[0997] (2) The following compound was obtained according to a similarmanner to that of Preparation 46-(5).

[0998] 3-[(1,4-Benzodioxan-6-yl)methyl]-2,5-piperazinedione NMR(DMSO-d₆, δ): 2.75 (1H, dd, J=13.6, 4.9Hz), 2.94 (1H, m), 3.00 (1H, m),3.43 (1H, dd, J=17.4, 2.7Hz), 3.97 (1H, m), 4.20 (4H, s), 6.57-6.77 (3H,m), 7.93 (1H, s), 8.10 (1H, m)

[0999] MASS (APCI): 263 (M+H)⁺

[1000] (3) To a stirred suspension of3-[(1,4-benzodioxan-6-yl)methyl]-2,5-piperazinedione (564 mg) intetrahydrofuran (100 ml) was added borane-tetrahydrofuran complex (1 Min tetrahydrofuran, 21 ml) by syringe under nitrogen atmosphere at roomtemperature and the mixture was heated under reflux for 18 hours. Aftercooling, the reaction mixture was filtered, and the filtrate was slowlyadded 12% hydrogen bromide in acetic acid (10 ml). To the mixture wasadded n-hexane (100 ml) and the whole was stirred for 1 hour at 5° C.The resulting precipitates were collected by filtration and dried underreduced pressure to give 2-[(1,4-benzodioxan-6-yl)methyl]piperazinedihydrobromide (831 mg) as a powder.

[1001] NMR (DMSO-d₆, δ): 2.62-3.80 (9H, m), 4.23 (4H, s), 6.71-6.88 (3H,m)

[1002] MASS (APCI): 235 (M+H)⁺ (free)

PREPARATION 48

[1003] (1) The following compound was obtained according to a similarmanner to that of Preparation 46-(4).

[1004]1-Acetyl-3-[(4-methoxy-3-methylphenyl)methylene]-2,5-piperazinedione

[1005] NMR (DMSO-d₆, δ): 2.17 (3H, s), 2.49 (3H, s), 3:83 (3H, s), 4.35(2H, s), 6.90 (1H, s), 6.94 (1H, d, J=15.7Hz), 7.32 (2H, m), 10.28 (1H,s)

[1006] MASS (APCI): 289 (M+H)⁺

[1007] (2) The following compound was obtained according to a similarmanner to that of Preparation 46-(5).

[1008] 3-(4-Methoxy-3-methylbenzyl)-2,5-piperazinedione

[1009] NMR (DMSO-d₆, δ): 2.09 (3H, s), 2.73-3.04 (3H, m), 3.34 (1H, m),3.75 (3H, s), 3.99 (1H, m), 6.81-6.97 (3H, m), 7.89 (1H, s), 8.11 (1H,m)

[1010] MASS (APCI): 249 (M+H)⁺

[1011] (3) The following compound was obtained according to a similarmanner to that of Preparation 47-(3).

[1012] 2-(4-Methoxy-3-methylbenzyl)piperazine dihydrobromide

[1013] NMR (DMSO-d₆, δ): 2.09 (3H, s), 2.60-3.72 (9H, m), 3.78 (3H, s),6.55 (2H, m), 6.87-7.14 (3H, m), 9.09 (2H, m)

[1014] MASS (APCI): 221 (M+H)⁺ (free)

PREPARATION 49

[1015] (1) The following compound was obtained according to a similarmanner to that of Preparation 46-(4).

[1016] 1-Acetyl-3-[(2,3-dimethoxyphenyl)methylene]-2,5-piperazinedione

[1017] IR (KBr): 1712, 1697, 1685, 1647, 1624, 1373, 271, 1225 cm⁻¹

[1018] NMR (DMSO-d₆, δ): 2.51 (3H, s), 3.74 (3H, s), 3.83 (3H, s), 4.35(2H, s), 7.03-7.16 (4H, m), 10.07

[1019] MASS (APCI): 305 (M+H)⁺

[1020] (2) A solution of1-acetyl-3-[(2,3-dimethoxyphenyl)-methylene]-2,5-piperazinedione (2.40g) in a mixed solvent of tetrahydrofuran (120 ml) and methanol (80 ml)was hydrogenated using 10% palladium-carbon (50% wet, 0.55 g) atatmospheric pressure for 3 hours. The catalyst was removed by filtrationand the filtrate was concentrated under reduced pressure. The resultingprecipitates were collected by filtration to give gray solid of1-acetyl-3-(2,3-dimethoxybenzyl)-2,5-piperazinedione (2.55 g).

[1021] IR (KBr): 3265, 1726, 1711, 1689, 1487, 1460, 1358, 1275, 1257cm⁻¹

[1022] NMR (DMSO-d₆, δ): 2.42 (3H, s), 2.90-3.20 (2H, m), 3.57-3.83 (1H,m), 3.72 (3H, s), 3.79 (3H, s), 4.14-4.23 (2H, m), 6.74-7.04 (3H, m),8.34 (1H, s)

[1023] MASS (APCI): 307 (M+H)⁺

[1024] (3) To a suspension of1-acetyl-3-(2,3-dimethoxybenzyl)-2,5-piperazinedione (2.49 g) intetrahydrofuran (38 ml) was added hydrazine monohydrate (0.43 ml) atroom temperature and the mixture was stirred at the same temperature for30 minutes. The resulting precipitates were collected by filtration andwashed with tetrahydrofuran to give -oowders of3-(2,3-dimethoxybenzyl)-2,5-piperazinedione (1.40 g).

[1025] IR (KBr): 3195, 3053, 1682, 1658, 1460, 1271, 1078 cm⁻¹

[1026] NMR (DMSO-d₆, δ): 2.87-3.09 (2H, m), 3.42-3.54 (2H, m), 3.73 (3H,s), 3.79 (3H, s), 3.88-3.96 (1H, m), 6.73-7.02 (3H, m), 7.94-8.00 (2H,m)

[1027] MASS (APCI): 265 (M+H)⁺

[1028] (4) A suspension of 3-(2,3-dimethoxybenzyl)-2,5-piperazinedione(1.26 g) in a mixed solvent of tetrahydrofuran (50 ml) and1,2-dimethoxyethane (50 ml) was heated at 60° C. with stirring andlithium aluminum hydride (0.905 g) was added thereto portionwisecarefully. After the reaction mixture was heated at 70° C. with stirringfor 3 hours, lithium aluminum hydride (0.20 g) and tetrahydroLuran (30ml) were added thereto again and the suspension was stirred at the sametemperature for 12 hours. After being cooled with ice-water, the mixturewas quenched by sequential addition of water (1.3 ml), 15% aqueoussodium hydroxide (1.3 ml), water (3.8 ml) and the whole was stirred atroom temperature for 2 hours. The resulting insoluble materials wereremoved by filtration and the filtrate was dried over sodium sulfate,and evaoorated under reduced pressure to give light yellowish oil of2-(2, 3-dimethoxybenzyl)piperazine (0.97 g)

[1029] IR (KBr): 2941, 1481, 1475, 1275, 1080 cm⁻¹

[1030] NMR (DMSO-d₆, δ): 2.07-3.60 (9H, m), 3.69 (3H, s), 3.78 (3H, s),6.71-7.00 (3H, m)

[1031] MASS (APCI): 237 (M+H)⁺

[1032] (5) A solution of benzyloxycarbonyl chloride (0.59 g) indichloromethane (3.0 ml) was added dropwise to a solution of2-(2,3-dimethoxybenzyl)piperazine (0.91 g) and triethylamine (0.64 ml)in dichloromethane (18 ml) below 5° C. over 5 minutes under ice-cooling,and the reaction mixture was stirred at the same temperature for 15minutes. After 2 hours of stirring at room temperature, the mixture waspoured into a mixed solvent of water (40 ml) and dichioromethane (25 ml)and the whole was adjusted to pH 9 witn aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with brine,dried over sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatoaraphy on silica gel (20 g) usinga mixed solvent of dichloromethane and methanol (40:1). The fractionscontaining the objective compound were collected and evaporated underreduced pressure to give colorless oil of1-(benzyloxycarbonyl)-3-(2,3-dimethoxybenzyl)piperazine (0.68 g)

[1033] IR (KBr):1714, 1699, 1685, 1273, 1244, 1225 cm ¹

[1034] NMR (CDCl₃, δ): 1.71 (1H, s), 2.23-3.00 (9H, m), 3.82 (3H, s),3.86 (3H, s), 5.13 (2H, s), 6.74-7.03 (3H, m), 7.34 (5H, s)

[1035] MASS (APCI): 371 (M+H)⁺

PREPARATION 50

[1036] A solution of1-[3,5-bis(trifluoromethyl)benzoyl]-4-(benzyloxycarbonyl)-2-(2,3-dimethoxybenzyl)piperazine(0.81 g) in methanol (20 ml) was hydrogenated over 10% palladium-carbon(50% wet, 0.30 g) at room temperature under atmospheric rressure for 90minutes. After removal of the catalyst by filtration, the filtrate wasevasorated under reduced pressure to give colorless oil of1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2,3-dimethoxybenzyl)-piperazine(0.64 g).

[1037] IR (KBr): 1645, 1635, 1281, 1184, 1134 cm⁻¹

[1038] NMR (CDCl₃, δ): 2.60-5.30 (10H, m), 3.81 (3H, S), 3.82 (3H, s),6.40-7.10 (3H, m), 7.20-8.49 (3H, m)

[1039] MASS (APCI): 477 (M+H)⁺

PREPARATION 51

[1040] (1) The following compound was obtained according to a similarmanner to that of Preparation 46-(4).

[1041] 1-Acetyl-3-[(1H-indol-2-yl)methylene]-2,5-piperazinedione

[1042] IR (KBr): 3332, 1714, 1685, 1668, 1419, 1221 cm⁻¹

[1043] NMR (DMSO-d₆, δ): 2.50 (3H, s), 4.38 (2H, s), 6.52-8.91 (6H, m),9.84-12.00 (2H, br)

[1044] MASS (APCI): 284 (M+H)⁺

[1045] (2) The following compound was obtained according to a similarmanner to that of Preparation 49-(2)

[1046] 1-Acetyl-3-[(1H-indol-2-yl)methyl]-2,5-piperazinedione

[1047] IR (KBr): 3325, 1730, 1697, 1682, 1653, 1456, 1205 cm⁻¹

[1048] NMR (DMSO-d₆, δ): 2.43 (3H, s), 2.80-5.25 (5H, m), 6.18-8.73 (6H,m), 10.96 (1H, s)

[1049] MASS (APCI): 286 (M+H)⁺

[1050] (3) The following compound was obtained according to a similarmanner to that of Preparation 49-(3)

[1051] 3-[(1H-Indol-2-yl)methyl]-2,5-piperazinedione

[1052] IR (KBr): 3363, 3317, 1682, 1645, 1456, 1323 cm⁻¹

[1053] NMR (DMSO-d₆, δ): 3.03-3.61 (4H, m), 4.09-4.15 (1H, m), 6.18 (1H,s), 6.89-7.05 (2H, m), 7.31 (1H, d, J=7.9Hz), 7.43 (1H, d, J=7.2Hz),7.99 (1H, s), 8.11 (1H, s), 10.85 (1H, s)

[1054] MASS (APCI): 244 (M+H)⁺

[1055] (4) The following compound was obtained according to a similarmanner to that of Preparation 49-(4).

[1056] 2-[(1H-Indol-2-yl)methyl]piperazine

[1057] IR (KBr): 3305, 2941, 1653, 1456 cm⁻¹

[1058] NMR (DMSO-d₆, δ): 80-3.70 (11H, m), 6.12 (1H, s), 6.87-7.02 (2H,m), 7.27 (1H, d, J=7.9Hz), 7.40 (1H, d, J=6.9Hz), 10.89 (1H, s)

[1059] MASS (APCI): 216 (M+H)⁺

[1060] (5) The following compound was obtained according to a similarmanner to that of Preparation 49-(5)

[1061] 1-(Benzyloxycarbonyl)-3-[(1H-indol-2-yl)methyl]-piperazine

[1062] IR (KBr): 3303, 2908, 1697, 1684, 1456, 1433, 1248 cm⁻¹

[1063] NMR (DMSO-d₆, δ): 2.34-2.90 (8H, m), 3-78-3.89 (2H, m), 5.03 (2H,s), 6.17 (1H, s), 6.90-7.04 (2H, m), 7.26-7.43 (7H, m), 10.93 (1H, s)

[1064] MASS (APCI): 350 (M+H)⁺

PREPARATION 52

[1065] The following compound was obtained according to a similar mannerto that of Preparation 50.

[1066]1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-2-yl)-methyl]piperazine

[1067] IR (KBr): 1653, 1647, 1635, 1281, 1184, 1136 cm ⁻¹

[1068] NMR (DMSO-d₆, δ): 2.50-4.90 (10H, m), 5.98-6.28 (1H, m),6.90-7.42(5H, m), 7.76-8.48 (2H, m), 10.59-11.03 (1H, m)

[1069] MASS (APCI): 456 (M+H)⁺

PREPARATION 53

[1070] (1) The following compound was obtained according to a similarmanner to that of Preparation 46-(4).

[1071] 1-Acetyl-3-(3-methoxyphenyl)methylene-2,5-piperazinedione

[1072] NMR (DMSO-d₆, δ): 2.50 (3H, s), 3.79 (3H, s), 4.36 (2H, s),6.9-7.0 (2H, m), 7.1-7.2 (2H, m), 7.3-7.4 (1H, m), 10 4 (1H, br s)

[1073] MASS (APCI): 275 (M+H)⁺

[1074] (2) The following compound was obtained according to a similarmanner to that of Preparation 49-(2).

[1075] 1-Acetyl-3-(3-methoxybenzyl)-2,5-piperazinedione

[1076] NMR (DMSO-d₆, δ): 2.42 (3H, s), 2.9-3.1 (2H, m), 3.33 (1H, d,J=17Hz), 3.71 (3H, s), 4.02 (1H, d, J=17Hz), 4.3-4.4 (1H, m), 6.7-6.9(3H, m), 7.1-7.3 (1H, m), 8.43 (1H, br s)

[1077] MASS (APCI): 277 (M+H)⁺

[1078] (3) The following compound was obtained according to a similarmanner to that of Preparation 49-(3).

[1079] 3-1(3-Methoxybenzyl)-2,5-piperazinedione

[1080] NMR (DMSO-d₆, δ): 2.8-3.5 (4H, m), 3.71 (3H, s), 4.0-4.1 (1H, m),6.7-6.9 (3H, m), 7.1-7.3 (1H, m), 7.91 (1, br s), 8.13 (1H, br s)

[1081] MASS (APCI): 235 (M+H)⁺

[1082] (4) The following compound was obtained according to a similarmanner to that of Preparation 49-(4).

[1083] 2- (3-Methoxybenzyl)piperazine

[1084] NMR (DMSO-d₆, δ): 2.2-2.9 (9H, m), 3.5-3.8 (2H, m), 3.73 (3H, s),6.7-6.8 (3H, m), 7.1-7.3 (1H, m)

[1085] MASS (APCI): 207 (M+H)⁺

[1086] (5) A solution of di-tert-butyl dicarbonate (1.99 g) intetrahydrofuran (20 ml) was added dropwise to a mixture of2-(3-methoxybenzyl)piperazine (1.88 g) and triethylamine (1.90 ml) intetrahydrofuran ( 19ml) with ice-water cooling. After 1 hour ofstirring, ethyl acetate (100 ml) and water (50 ml) were added to themixture. The organic layer was separated, washed with brine, dried oversodium sulfate, and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel using a mixture of dichloromethaneand methanol (40:1) to give2-(3-methoxybenzyl)-4-(tert-butoxycarbonyl)-piperazine (1.18 g) as anoil.

[1087] NMR (DMSO-d₆, δ): 1.34 (9H, s), 2.1-2.9 (8H, m), 3.6-3.8 (2H, m),3.73 (3H, s), 6.7-6.8 (3H, m), 7.1-7.3 (1H, m)

[1088] MASS (APCI): 307 (M+H)⁺

[1089] (6) The following compound was obtained according to a similarmanner to that of Example 86.

[1090]1-[3,5-Bis(trifluoromethyl)benzoyl]-4-tert-butoxycarbonyl-2-(3-methoxybenzyl)piperazine

[1091] NMR (DNSO-d₆, δ): 1.44 (9H, s), 2.5-5.0 (12H, m), 6.5-8.3 (7H, m)

[1092] MASS (APCI): 447 (M+H)⁺

[1093] (7) The following compound was obtained according to a similarmanner to that of Preparation 35.

[1094]1-[3,5-Bis(trifluoromethyl)benzoyl]-3-(3-methoxybenzyl)-piperazinehydrochloride

[1095] NMR (DMSO-d₆, δ): 2.7-5.2 (12H, m), 6.4-8.3 (7H, m), 9.4-10.2(2H, m)

[1096] MASS (APCI): 447 (M+H)⁺ (free)

PREPARATION 54

[1097] (1) 3,4-Dimethylbenzyl chloride (10.2 g) and diethylacetamidomalonate (14.3 g) were added successively into a solution ofsodium ethoxide (4.94 g) in ethanol. The mixture was stirred underreflux for 2 hours and filtered through Celite®. The filtrate wasconcentrated under reduced pressure to give crystals which werecollected by filtration and washed with isopropyl ether to givecolorless crystals of diethyl2-acetylamino-2-(3,4-dimethylbenzyl)malonate (11.8 g).

[1098] mp: 107-109° C.

[1099] IR (KBr): 3335, 3275, 1750, 1645, 1520, 1460, 1380, 1280, 1185cm⁻¹

[1100] NMR (DMSO-d₆, δ): 1.17 (6H, t, J=7.2Hz), 1.90-1.93 (3H, m),2.02-2.20 (6H, m), 3.30-3.50 (3H, m), 4.14 (2H, q, J=7.2Hz), 6.60-7.05(3H, m), 7.97, 8.07 (1H, 2s)

[1101] MASS (EI): 335 (M)⁺, 276, 119

[1102] (2 Diethyl 2-acetylamino-2-(3,4-dimethylbenzyl)malonate (13.8 g)and potassium hydroxide (2.76 g) were dissolved into a mixed solution ofethanol (138 ml) and water (138 ml) and the solution was stirred underreflux for 8.5 hours. After being cooled to room temperature, thesolution was concentrated under reduced pressure and the resultingaqueous solution was adjusted to pH 10 with aqeucus saturated sodiumhydrogen carbonate solution. The solution was washed with ethyl acetateand made acidic with diluted hydrochloric acid, and extracted with ethylacetate. The extract was dried over magnesium sulfate and evaporatedunder reduced pressure to give crystals ofN-acetyl-3,4-dimethyl-DL-phenylalanine (5.42 g).

[1103] mp: 136-139° C.

[1104] IR (Nujol): 3337, 2700-2400, 1710, 1610, 1540, 1450, 1380, 1355cm⁻¹

[1105] NMR (DMSO-d₆, δ): 1.67 (3H, s), 2.17-2.21 (6H, m), 2.60-3.15 (2H,m), 4.25-4.40 (1H, m), 6.90-7.05 (3H, m), 8.10-8.25 (1H, m)

[1106] MASS (EI): 235 (M)⁺, 176, 119

[1107] (3) N-Acetyl-3,4-dimethylphenyl-DL-alanine (498.0 g) wasdissolved into a mixture of 1N sodium hydroxide (2.12 L) and water (2.49L). Cobalt dichloride hexahydrate (2.49 g) and acylase (Acylase Amano15000, 24.9 g) were added to the solution and the mixture was stirred at37° C. for 20 hours with controlling the pH of the reaction mixture to7.5 with 1N sodium hydroxide. The resulting precipitates were collectedby filtration and washed with water (500 ml×2) to give crystals ofL-3,4-dimethylphenylalanine (120.7 g). The pH of the filtrate wasadjusted to 1 with aqueous diluted hydrochloric acid and the solutionwas extracted with ethyl acetate. The extract was dried over magnesiumsulfate and evaporated under reduced pressure to give a solid ofN-acetyl-3,4-dimethylphenyl-D-alanine (160.72 g).

[1108] mp: 156-159° C.

[1109] IR (Nujol): 3400, 3350, 2500-2400, 1710, 1620, 1560, 1450 cm⁻¹

[1110] NMR (DMSO-d₆, δ): 1.78 (3H, s), 2.16 (6H, s), 2.68-3.20 (2H, m),4.28-4.40 (1H, m), 6.90-7.05 (3H, m), 8.18 (1H, d, J=8.0Hz), 12.61 (1H,s)

[1111] MASS (EI): 235 (M)⁺, 176, 119

[1112] (4) A solution of N-acetyl-3,4-dimethylphenyl-D-alanine (5.0 g)in a mixture of concentrated hydrochloric acid (50 ml) and acetic acid(50 ml) was stirred under reflux for 20 hours. After being cooled toroom temperature, the resulting precipitates were collected byfiltration and washed with ethyl acetate to give colorless crystals of3,4-dimethylphenyl-D-alanine hydrochloride (3.75 g).

[1113] mp: >250° C.

[1114] [α]_(D) ²⁶: −3.30 (C=1.0, MeOH)

[1115] IR (Nujol): 2800-2400, 1730, 1600, 1500, 1480 cm⁻¹

[1116] NMR (DMSO-d₆, δ): 2.19 (6H, s), 3.07 (2H, d, J=6.2Hz), 4.07 (1H,t, J=6.2Hz), 6.90-7.10 (3H, m), 8.30-8.60 (3H, m)

[1117] MASS (APCI): 194 (M+H)⁺ (free)

[1118] (5) Thionyl chloride (5.4 ml) was added dropwise to methanol (60ml) below 5° C. with ice-salt bath cooling and stirring was continuedfor 10 minutes at the same temperature. 3,4-Dimethylphenyl-D-alaninehydrochloride (5.0 g) was added to the mixture by small portions over 20minutes at −15° C. and the whole was stirred at room temperature for 6hours, and evaporated under reduced pressure. The resulting solid wastriturated with isopropyl ether to give colorless crystals of3,4-dimethyluhenyl-D-alanine methyl ester hydrochloride (5.10 g).

[1119] mp: 90.0-190.5° C.

[1120] [α]_(D) ³⁰: −10.36° (C=0.55, MeOH)

[1121] IR (Nujol): 3400, 1735 cm⁻¹

[1122] NMR (DMSO-d₆, δ): 2.19 (6H, s), 3.03 (1H, dd, J=7.3, 14.0Hz),3.15 (1H, dd, J=5.7 14.0Hz), 3.66 (3H, s), 4.16 (1H, dd, J=7.3, 5.7Hz),6.93 (1H, d, J=7.6Hz), 6.99 (1H, s), 7.08 (1H, d, J=7.6Hz), 8.78 (3H, s)

[1123] MASS (APCI): 208 (M+H)⁺ (free)

[1124] (6) Potassium carbonate (5.45 g) was added by small portions withice-coolina to a mixture of 3,4-dimethylphenyl-D-alanine methyl esterhydrochloride (4.81 g) In a mixed solvent of dichloromethane and water.Chloroacetyl chloride (2.20 ml) was added to the mixture below 5° C.over 10 minutes and the whole was stirred for 30 minutes. The organiclayer was separated, washed with brine, dried over magnesium sulfate,and evaporated under reduced pressure to give an oil of methyl(2R)-2-(2-chloroacetylamino)-3-(3,4-dimethylphenyl)-propionate (6.01 g).

[1125] IR (Neat): 3400, 1735, 1650, 1460 cm⁻¹

[1126] NMR (CDCl₃, δ): 2.22 (6H, s), 3.08 (1H, d, J=5.7Hz), 3.74 (3H,s), 4.02 (2H, s), 4.77-4.87 (1H, m), 6.80-7.10 (4H, m)

[1127] MASS (APCI): 283 (M+H)⁺, 441

[1128] (7) Benzylamine (5.4 ml) and potassium carbonate (4.08 g) wereadded successively to a solution of methyl(2R)-2-(2-chloroacetylamino)-3-(3,4-dimethylphenyl)propionate (5.33 g)in N,N-dimethylformamide (25 ml) at 20° C. After 3 hours of stirring at35° C., the mixture was poured into a mixture of ice-water (40 ml) anddichloromethane (40 ml). After the mixture was adjusted to pH 6 withconcentrated hydrochloric acid (ca. 1.4 ml), the organic layer wasseparated, washed with brine (20 ml), dried over magnesium sulfate, andevaporated under reduced pressure. The residue was triturated withn-hexane and filtered to give colorless powders of(3R)-1-benzyl-3-(3,4-dimethylbenzyl)-2,5-piperazinedione (1.51 g). Thefiltrate was evaporated under reduced pressure to give an oil of methyl(2R)-2-[(2-benzylaminoacetyl)amino]-3-(3,4 -dimethylphenyl)propionate(5.67 g)

[1129] IR (Neat) 3400, 1735, 1650, 1460 cm⁻¹

[1130] NMR (CDCl₃, δ): 2.12-2.21 (6H, m), 3.04-3.10 (2H, m), 3.29 (2H,d, J=2.0Hz), 3.66 (2H, s), 3.74 (3H, s), 4.80-4.90 (1H, m), 6.80-7.40(9H, m), 7.90-8.05 (1H, m)

[1131] MASS (APCI): 355 (M+H)⁺

[1132] (8) A mixture of methyl(2R)-2-[(2-benzylaminoacetyl)amino]-3-(3,4-dimethylphenyl)propionate(2.5 g) and acetic acid (0.2 ml) in isopropyl alcohol (8.8 ml) wasstirred for 5 hours under reflux. After being cooled to roomtemperature, isopropyl ether was added to the mixture. The resultingprecipitates were collected by filtration and washed with isopropylether to give colorless crystals of(3R)-1-benzyl-3-(3,4-dimethylbenzyl)-2,5-piperazinedione (1.26 g).

[1133] mp: 191-192° C.

[1134] [α]_(D) ²⁵: −23.3° (C=1, DMF)

[1135] IR (Nujol): 3180, 1640, 1500, 1340 cm⁻¹

[1136] NMR (DYSO-d₆, δ): 2.11 and 2.16 (3H, 2s), 2.82 (1H, dd, J=4.8,13.5Hz), 3.13 (1H, dd, J=4.2, 13.5Hz), 2.76 (1H, d, J=17.1Hz), 3.46 (1H,d, J=17.1Hz), 4.22 (1H, d, J=14.5Hz), 4.55 (1H, d, J=14.5Hz), 4.2-4.3(1H, m), 6.7-6.9 (3H, m), 7.0-7.1 (2H, m), 7.2-7.3 (3H, m), 8.31 (1H, s)

[1137] MASS: 323 (M+1)

[1138] (9) The following compound was obtained according to a similarmanner to that of Preparaticn 49-(4).

[1139] (3R)-1-Benzyl-3-(3,4-dimethylbenzyl)piperazine

[1140] IR (Neat): 3000-2750, 1670, 1500, 1450, 1360, 1320 cm ⁻¹

[1141] NMR (CDCl₃, δ): 2.26 (6H, m), 1.8-3.0 (9H, m), 3.4-3.6 (2H, m),6.9-7.1 (3H, m), 7.2-7.5 (5H, m)

[1142] MASS: 295 (M+1) its hydrochloride

[1143] mp: 186-188° C.

[1144] [α]_(D) ^(29.2): +12.72° (C=0.55, MeOH)

[1145] IR (Nujol):3500, 2350 cm⁻¹

[1146] NMR (DMSO-d₆, δ): 2.20 (6H, s), 2.73-3.90 (9H, m), 4.34 (1H, d,J=13.1Hz), 4.42 (1H, d, J=13.1Hz), 6.97 (1H, d, J=7.6Hz), 7.02 (1H, s),7.11 (1H, d, J=7.6Hz), 7.36-7.65 (5H, m)

[1147] MASS (APCI): 295 (M+H)⁺ (free)

[1148] (10) The following compound was obtained according to a similarmanner to that of Example 86.

[1149] (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-benzylpiperazine

[1150] IR (Neat): 3000-2700, 1640, 1500, 1430, 1350 cm⁻¹

[1151] NMR (CDCl₃, δ): 2.1-2.3 (6H, m), 2.1-2.2 (2H, m), 2.6-3.7 (8H,m), 4.5-5.1 (1H, m), 6.5-6.7 (2H, m), 6.9-7.6 (7H, m), 7.8-7.9 (2H, m)

[1152] MASS: 535 (M+1)

[1153] (11) A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dlmethylbenzyl)-4-benzylpiperazine(2.94 g), ammonium formate (1.74 g) and 10% palladium-carbon (0.58 g) ina mixed solvent of methanol (11.8 ml), water (5.9 ml) andtetrahydrofurane (10 ml) was stirred for 5.5 hours at 50° C. undernitrogen atmosphere. The reaction mixture was cooled to room temperatureand filtered through Celite® pad. The filtrate was concentrated underreduced pressure and the residue was dissolved in ethyl acetate. Thesolution was washed with water and brine, dried over magnesium sulfate,and evaporated under reduced pressure. The residue was dissolved inmethanol and treated with fumaric acid (468 mg) to give colorless powderof fumaric acid salt (1:1) of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-piperazine(0.24 g).

[1154] mp: 186-188° C.

[1155] [α]_(D) ³¹: −23.99° (C=0.55, MeOH)

[1156] IR (Nujol): 2320, 1720, 1705, 1630, 1270 cm⁻¹

[1157] NMR (DMSO-d₆, δ): 1.57-2.34 (6H, m), 2.56-5.08 (9H, m), 6.10-8.52(11H, m)

[1158] MASS (APCI): 445 (M+H)⁺ (free)

PREPARATION 55

[1159] (1) Benzaldehyde (17.4 ml) was added dropwise to a solution of2-amino-2-methyl-1,3-propanediol (20 g) in methanol (200 ml) at 0° C.and the whole was stirred at room temperature for 2 hours. Sodiumborohydride (11.5 g) was added thereto in portions at 0° C. and themixture was stirred for 10 minutes. 1N Sodium hydroxide solution andethyl acetate were added and the organic layer was separated, dried overmagnesium sulfate, and evaporated in vacuo to give2-benzylamino-2-methyl-1,3-propanediol (28.54 g).

[1160] NR (CDCl₃, δ): 1.08 (3H, s), 3.54 (4H, s), 3.73 (2H, s),7.20-7.45 (5H, m)

[1161] MASS (APCI): 196 (M+H)⁺

[1162] (2) Chloroacetyl chloride (14.0 ml) was added dropwise to amixture of 2-benzylamino-2-methyl-1,3-propanediol (28.5 g), potassiumcarbonate (30.3 g) in dlchloromethane (150 ml) and water (1.50 ml) at0°° C., and the whole was stirred at room temperature for 2 hours. Themixture was extracted with dichloromethane and the extract was washedsuccessively with water, 1N hydrochloric acid and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was dissolved intert-butanol (400 ml) and the solution was added potassium tert-butoxide(16.38 g) portionwisely and the whole was refluxed for 30 minutes. Aftercooling, the solvent was removed by evaporation and ethyl acetate andwater were added thereto. The organic layer was separated, dried overmagnesium sulfate, and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel with a mixture of ethyl acetate andn-hexane (1:1) as an eluent to give4-benzyl-5-hydroxymethyl-5-methyl-3-morpholinone (10.89 g).

[1163] NMR (CDCl₃, δ): 1.12 (3H, s),2.50 (1H, br s), 3.44 (1H, d,J=11.7Hz), 3.56 (1H, d, J=11.9Hz), 3.67 (1H, d, J=11.7Hz), 3.98 (1H, d,J=11.9Hz), 4.29 (2H, s), 4.67 (2H, s), 7.10-7.40 (5H, m)

[1164] MASS (APCI): 236 (M+H)⁺

[1165] (3) Sodium bis(2-methoxyethoxy)aluminum hydride (3.46 M solutionin toluene; 42 ml) was added to a solution of4-benzyl-5-hydroxymethyl-5-methyl-3-morpholinone (10.77 g) in toluene(100 ml) at 0° C. under nitrogen atmosphere and the whole was stirred atroom temperature for 1 hour. Ethanol (20 ml) was added to the mixture at0° C. and the pH of the mixture was adjusted to 12 by 1N sodiumhydroxide solution. The organic layer was separated, added 1Nhydrochloric acid and the acidic aqueous layer was separated. Thisprocedure was repeated twice and the combined aqueous layer was madealkaline with 4 M sodium hydroxide solution. It was extracted with ethylacetate, dried over magnesium sulfate and evaporated in vacuo to give4-benzyl-3-hydroxymethyl-3-methylmorpholine (9.35 g) as an oil.

[1166] NMR (CDCl₃, δ): 1.12 (3H, s), 2.50-2.64 (2H, m), 3.10-4.05 (8H,m), 7.20-7.50 (5H, m)

[1167] MASS (APCI): 222 (M+H)⁺

[1168] (4) A solution of 4-benzyl-3-hydroxymethyl-3-methylmorpholine (1g) in tetrahydrofuran (10 ml) was added dropwise to a suspension ofsodium hydride (60% oil suspension; 0.27 g) in tetrahydrofuran (20 ml)at room temperature under nitrogen atmosphere and the whole was stirredat 70° C. for 1 hour. After cooling, methyl iodide (0.34 ml) was addedto the mixture and the whole was stirred at 40° C. for 1 hour. Aftercooling, ethyl acetate and water were added to the mixture and theorganic layer was separated, dried over magnesium sulfate and evaporatedin vacuo. The residue was purified by column chromatography on silicagel with a mixture of ethyl acetate and n-hexane (1:4) as an eluent togive 4-benzyl-3-methoxymethyl-3-methylmorpholine (0.77 g) as an oil.

[1169] NMR (CDCl₃, δ): 1.15 (3H, s), 2.30-2.64 (2H, m), 3.20-3.70 (8H,m), 3.36 (3H, s), 7.14-7.40 (5H, m)

[1170] MASS (APCI): 236 (M+H)⁺

[1171] (5) A solution of 4-benzyl-3-methoxymethyl-3-methylmorpholine(0.77 g) in methanol (20 ml) was hydrogenated in the presence of 10%palladium-carbon (80 mg) at room temperature. After 1 hour,palladium-carbon was removed by filtration and the filtrate wasevaporated in vacuo. The residue was dissolved in ethyl acetate (20 ml)and the solution was added 4N hydrogen chloride in ethyl acetate (4.08ml). The mixture was evaporated in vacuo to give3-methoxymethyl-3-methylmorpholine hydrochloride (0.4 g) as a whitesolid.

[1172] mp: 80-90° C.

[1173] IR (KBr): 3240-3270, 2976, 1090, 1049 cm⁻¹

[1174] NMR (DMSO-d₆, δ): 1.29 (3H, s), 3.00-3.92 (8H, m), 3.36 (3H, s)

[1175] MASS (APCI): 146 (M+H)⁺ (free)

PREPARATION 56

[1176] (1) A solution of (3R)-4-benzyl-3-hydroxymethylmorpholine (0.94g) in tetrahydrofuran (10 ml) was added drodwise to a suspension orsodium hydride (60% oil suspension, 0.22 g) in tetrahydrofuran (20 ml)at room temperature under nitrogen atmosphere and the whole was stirredat 70° C. for 1 hour. After cooling, methyl iodide (0.31 ml) was addedthereto and the mixture was stirred at 40° C. for 1 hour. After cooling,the mixture was poured into ice water, and extracted with ethyl acetate.The extract was dried over magnesium sulfate and evaporated in vacuo.The residue was purified by column chromatography on silica gel with amixture of ethyl acetate and n-hexane (3:7) as an eluent tosgive(3R)-4-benzyl-3-methoxymethylmorpholine (0.88 g) as an oil.

[1177] NMR (CDCl₃, δ): 2.20-2.40 (1H, m), 2.56-2.86 (2H, m), 3.26-4.26(8H, m), 3.34 (3H, s), 7.20-7.48 (5H, m)

[1178] MASS (APCI): 222 (M+H)⁺

[1179] (2) The following compound was obtained according to a similarmanner to that of Preparation 55-(5).

[1180] (3R) -3-Methoxymethylmorpholine hydrochloride

[1181] mp: 150-152° C.

[1182] [α]_(D) ²⁷: +16.31° (C=0.42, MeOH)

[1183] IR (KBr): 2964, 2947, 2929, 2897, 2887, 2835, 2810, 2789, 2765,2727, 2698, 2490, 1450, 1311, 1194, 1136, 1111, 1095 cm⁻¹

[1184] NMR (DMSO-d₆, δ): 2.94-3.24 (2H, m), 3.31 (3H, s), 3.36-3.78 (5H,m), 3.80-3.98 (2H, m), 9.52 (2H, br s)

[1185] MASS (APCI): 132 (M+H)⁺ (free)

PREPARATION 57

[1186] (1) The following compound was obtained according to a similarmanner to that of Preparation 56-(1).

[1187] (3S) -4-Benzyl-3-methoxymethylmorpholine NMR (CDCl₃, δ):2.15-2.34 (1H, m), 2.54-2.72 (2H, m), 3.33 (3H, s), 3.33 (1H, d,J=13.5Hz), 3.40-3.90 (6H, m), 4.07 (1H, d, J=13.5Hz), 7.18-7.40 (5H, m)

[1188] MASS (APCI): 222 (M+H)⁺

[1189] (2) The following compound was obtained according to a similarmanner to that of Prenaration 55-(5)

[1190] (35)-3-Methoxymethylmorpholine hydrochloride

[1191] mp: 150-152° C.

[1192] [α]_(D) ²⁷: −14.70° (C=0.50, MeOH)

[1193] IR (KBr): 2964, 2947, 2929, 2887, 2833, 2810, 2789, 2765, 2727,2698, 2490, 1450, 1311, 1194, 1136, 1111, 1095, 1041 cm⁻¹

[1194] NMR (DMSO-d₆, δ): 2.94-3224 (2H, m), 3.31 (3H, s), 3.38-3.75 (5H,m), 3.84-3.96 (2H, m), 9.45 (2H, br s)

[1195] MASS (APCI): 132 (M+H)⁺ (free)

PREPARATION 58

[1196] (1) The following compound was obtained according to a similarmanner to that of Preparation 56-(1).

[1197] (3S)-4-Benzyl-3-ethoxymethylmorpholine

[1198] NMR (CDCl₃, δ): 1.20 (3H, t, J=7.0Hz), 2.15-2.40 (1H, m),2.54-2.84 (2H, m), 3.24-4.20 (10H, m), 7.20-7.45 (5H, m)

[1199] MASS (APCI): 236 (M+H)⁺

[1200] (2) The following compound was obtained according to a similarmanner to that of Preparation 55-(5).

[1201] (3S)-3-Ethoxymethylmorpholine hydrochloride

[1202] mp: 100-115° C.

[1203] [α]_(D) ²⁷: −13.07° (C=0.505, MeOH)

[1204] IR (KBr): 2976, 2922, 2900, 2866, 2790, 2767, 2746, 2721, 2468,1458, 1450, 1435, 1309, 1176, 1147, 1126, 1101, 1043, 1030 cm⁻¹

[1205] NMR (DMSO-d₆, δ): 1.15 (3H, t, J=7.0Hz), 2.94-3.28 (2H, m),3.28-3.80 (7H, m), 3.80-4.00 (2H, m), 9.47 (2H, br s)

[1206] MASS (APCI): 146 (M+H)⁺ (free)

PREPARATION 59

[1207] The following compound was obtained according to a similar mannerto that of Preparation 55-(5).

[1208] (3S) -3-Hydroxymethylmorpholine hydrochloride

[1209] mp: 123-126° C.

[1210] [α]_(D) ²⁷: −15.80° (C=0.44, MeOH)

[1211] IR (KBr): 3290-3480, 2945, 1105, 1047 cm⁻¹

[1212] NMR (DMSO-d₆, δ): 2.86-4.00 (9H, m), 5.41 (1H, br s), 9.25 (1H,br s), 9.56 (1H, br s)

[1213] MASS (APCI): 118 (M+H)⁺ (free)

PREPARATION 60

[1214] (1) Hexafluoropropene diethylamine complex (1.58 ml) was addeddropwise to a solution of (3R)-4-benzyl-3-hydroxymethylmorpholine (1.5g) in dichloromethane (100 ml) at −30° C. under nitrogen atmosphere andthe whole was stirred at room temperature for 3 hours. The solution waswashed with water and saturated sodium hydrogen carbonate solution,dried over magnesium sulfate and evaporated in vacuo. The residue wasdissolved in methanol (100 ml) and the solution was added 30% sodiummethoxide solution in methanol (2.9 ml). After 30 minutes of stirring,acetic acid (0.9 ml) was added to the mixture and the whole wasevaporated in vacuo. Dichloromethane and water were added to the residueand the organic phase was separated, dried over magnesium sulfate, andevaporated in vacuo. The reside was purified by column chromatography onsilica gel to give a crude mixture (2.26 g) containing mainly(3R)-4-benzyl-3-fluoromethylmorpholine and4-benzyl-6-fluoroperhydro-1,4-oxazepine. The obtained mixture was usedto the next reaction without further purification.

[1215] (2) The crude mixture (2.2 g) obtained by the previous procedure,which contained mainly (3R)-4-benzyl-3-fluoromethylmorpholine and4-benzyl-6-fluoroperhydro-1,4-oxazepine, was dissolved in methanol (50ml). The solution was hydrogenated in the presence of 10%palladium-carbon (200 mg) at room temperature. After 1 hour of stirring,palladium-carbon was removed by filtration and the filtrate wasevaporated under reduced pressure. The two isomers were separated bycolumn chromatography using 2% of methanol in dichloromethane as aneluent to give (3R)-3-fluoromethylmorpholine and6-fluoroperhydro-1,4-oxazepine (the former was less polar). The productswere converted to their hydrochloride as a conventional manner using 4Nhydrogen chloride in ethyl acetate, respectively.

[1216] (3R)-3-Fluoromethylmorpholine hydrochloride (0.21 g)

[1217] NMR (DMSO-d₆, δ): 3.02-3.34 (2H, m), 3.48-3.82 (3H, m), 3.82-4.10(2H, m), 4.57 (1H, d, J=4.0Hz), 4.80 (1H, d, J=4.0Hz), 9.84 (2H, br s)

[1218] MASS (APCI): 120 (M+H)⁺ (free)

[1219] 6-Fluoroperhydro-1,4-oxazepine hydrochloride (0.26 g)

[1220] NMR (DMSO-d₆, δ): 3.10-3.32 (2H, m), 3.40-3.60 (2H, m), 3.68-4.16(4H, m), 4.94-5.30 (1H, m)

[1221] MASS (APCI): 120 (M+H)⁺ (free)

PREPARATION 61

[1222] Triphenylphosphine (7.31 g) was added to a solution of carbontetrabromide (4.62 g) in dichloromethane (15 ml) at 0° C. and themixture was stirred at 0° C. for 15 minutes. A solution of(3S)-4-tert-butoxycarbonyl-3-formylmorpholine (1.5 g) in dichloromethane(15 ml) was added dropwise to the solution over 10 minutes at 0° C. andstirred for 3 hours, and the mixture was added saturated sodium hydrogencarbonate solution. The organic layer was separated and the aqueouslayer was extracted with ethyl acetate three times. The combined organiclayer was washed with brine, dried over magnesium sulfate, andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using a mixture of ethyl acetate andn-hexane (4:6) to give(3R)-4-tert-butoxycarbonyl-3-(2,2-dibromoethenyl)-morpholine as an oil.

[1223] This oil was dissolved in tetrahydrofuran (15 ml) andbutyllithium (1.62 M in hexane, 9.45 ml) was added to the solution at−78° C. After 30 minutes of stirring at −78° C., the mixture wasquenched with water and extracted with ethyl acetate twice. The combinedorganic layer was washed with brine, dried over magnesium sulfate, andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using a mixture of ethyl acetate and hexane(2:8) to give (3R)-4-tert-butoxycarbonyl-3-ethynylmorpholine (1.385 g,as a pale yellow oil.

[1224] NMR (CDCl₃, δ): 1.48 (99H, s), 2.31 (1H, d, J=2.3Hz), 3.19-3.96(6H, m), 4.74 (1H, br s)

[1225] MASS (APCI): 112 (M-Boc)⁺

PREPARATION 62

[1226] (1) The following compound was obtained according to a similarmanner to that of Preparation 55-(5).

[1227] (3S)-3-Ethoxycarbonylmorpholine hydrochloride

[1228] NMR (CDCl₃, δ): 1.33 (3H, t, J=7.1Hz), 3.20-3.75 (2H, m),3.90-4.30 (5H, m), 4.32 (2H, q, J=7.1Hz), 10.04 (1H, br s), 10.74 (1H,br s)

[1229] MASS (APCI): 160 (M+H)⁺ (free)

[1230] (2) A mixture of (3S)-3-ethoxycarbonylmorpholine hydrochloride(0.3 g), propargyl bromide (0.34 ml) and potassium carbonate (0.91 g) inN,N-dimethylformamide (10 ml) was stirred at room temperature for 1 hourand then the solvent was removed under reduced pressure. Ethyl acetateand sodium hydrogen carbonate solution were added to the residue and theorganic layer was separated, dried over magnesium sulfate, andevaporated in vacuo. The residue was purified by column chromatographyon silica gel with a mixture of ethyl acetate and n-hexane (3:7) as aneluent to give (3S)-3-ethoxycarbonyl-4-(2-propynyl)morpholine (0.22 g)as an oil.

[1231] NMR (CDCl₃, δ): 1.29 (3H, t, J=7.1Hz), 2.28 (1H, t, J=2.5Hz),2.70-2.95 (2H, m), 3.40-4.05 (7H, m), 4.21 (2H, q, J=7.1Hz)

[1232] MASS (APCI): 198 (M+H)⁺

PREPARATION 63

[1233] (1) Sodium triacetoxyborohydride (4.63 g) was added portionwiselyto a mixture of (R)-(−)-2-amino-1-butanol (1.5 g) and benzaldehyde (1.79g) in dichloromethane (50 ml) at 0° C. and the whole was stirred at roomtemperature overnight. The mixture was washed with sodium carbonatesolution and brine, dried over sodium sulfate, and evaporated in vacuoto give (R)-2-benzylamino-1-butanol (2.69 g) [IR (Neat): 3292, 1460,1350, 1136, 1061 cm⁻¹]. A solution of chloroacetyl chloride (2.1 g) intetrahydrofuran (4 ml) was added to a mixture of the obtained oil (2.69g) and potassium carbonate (4.6 g) in a mixture of acetone (20 ml) andwater (20 ml) at 0° C. After 1 hour of stirring, the solvent wasreplaced with ethyl acetate. The organic layer was separated, washedwith brine, dried over sodium sulfate, and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel to giveN-benzyl-N-[(2R)-2-(1-hydroxybutyl)]-2-chloroacet amide (2.73 g) [IR(Neat): 3430, 1640, 1450, 1420, 1355, 1045 cm¹, MASS (APCI): 256 (M+H)⁺,220] as an oil. Potassium tert-butoxide (1.22 g) was added to a solutionof the above obtained oil (2.7 g) in tert-butanol (20 ml) portionwiselyat room temperature and the whole was stirred overnight. The mixture wasevaporated in vacuo, and ethyl acetate and water were added to theresidue. The organic layer was separated, washed with brine, dried oversodium sulfate, and evaporated in vacuo to give(5R)-4-benzyl-5-ethyl-3-morpholinone (2.33 g) as an oil.

[1234] IR (Neat) 1655, 1640, 1450, 1430, 1360, 1340, 1260, 1155, 1128cm⁻¹

[1235] NMR (CDCl₃, δ): 0.91 (3H, t, J=7.5Hz), 1.60-1.96 (2H, m),2.94-3.14 (1H, m), 3.55-3.94 (2H, m), 3.92 (1H, d, J=15.0Hz), 4.21 (1H,d, J=16.7Hz), 4.31 (1H, d, J=16.7Hz), 5.43 (1H, d, J=15.0Hz), 7.20-7.44(5H, m)

[1236] MASS (APCI): 220 (M+H)⁺

[1237] (2) A solution of (5R)-4-benzyl-5-ethyl-3-morpholinone (2.3 g) intetrahydrofuran (7 ml) was added portionwisely to a suspension oflithium aluminum hydride (0.4 g) in tetrahydrofuran (15 ml) and thewhole was refluxed for 2 hours. After cooling, 50% aqueoustetrahydrofuran solution (4 ml) was added thereto and stirring wascontinued for 15 minutes. The mixture was filtered through Celite® pad,and the pad was washed with tetrahydrofuran. The combined filtrate wasevaporated in vacuo and the residue was purified by columnchromatography on silica gel to give (3R)-4-benzyl-3-ethylmorpholine(1.44 g) as an oil.

[1238] IR (Neat): 1495, 1450, 1355, 1130, 1060 cm⁻¹

[1239] NMR (CDCl₃, δ): 0.93 (3H, t, J=7.5Hz), 1.44-1.94 (2H, m),2.08-2.45 (2H, m), 2.54-2.70 (1H, m), 3.15 (1H, d, J=13.3Hz), 3.55-3.86(4H, m), 4.06 (1H, d, J=13.3Hz), 7.15-7.40 (5H, m)

[1240] MASS (APCI): 205 (M+H)⁺

[1241] A solution of the obtained oil (1.44 g) in ethanol (15 ml) washydrogenated using 10% palladium-carbon (200 mg) at atmosphericpressure. After the reaction was completed (7 hours), the catalyst wasremoved by filtration. The filtrate was added 4N hydrogen chloride inethyl acetate (2.5 ml) and the whole was evaporated in vacuo. Theresidue was triturated with ethyl acetate and the resulting precipitateswere collected by filtration and dried to give (3R)-3-ethylmorpholinehydrochloride (1.0 g).

[1242] mp: 223-225° C.

[1243] [α]_(D) ²⁸: +9.50 (C=0.5, MeOH)

[1244] IR (KBr): 2729, 2696, 2472, 1458, 1427, 1360, 1313, 1109, 1061cm⁻¹

[1245] NMR (DMSO-d₆, δ): 0.93 (3H, t, J=7.5Hz), 1.40-1.78 (2H, m),2.88-3.55 (4H, m), 3.60-4.04 (3H, m), 9.60 (2H, br s)

[1246] MASS (APCI): 116 (M+H)⁺ (free)

PREPARATION 64

[1247] (1) The following compound was obtained according to a similarmanner to that of Preparation 63-(1).

[1248] (3S)-4-Benzyl-5-ethyl-morpholinone

[1249] IR (Neat): 1653, 1462, 1348, 1203, 1155, 1122 cm⁻¹

[1250] NMR (CDCl₃, δ): 0.91 (3H, t, J=7.5Hz) 1.60-1.96 (2H, m),2.95-3.14 (1H, m), 3.58-3.94 (2H, m), 3.92 (1H, d, J=15.0Hz), 4.21 (1H,d, J=16.7Hz), 4.30 (1H, d, J=16.7Hz), 5.43 (1H, d, J=15.0Hz), 7.15-7.44(5H,

[1251] MASS (APCI):220 (M+H)⁺

[1252] (2) The following compound was obzained according to a similarmanner to that of Preparation 63-(2).

[1253] (3S)-3-Ethylmorpholine hydrochloride

[1254] mp: 221-224° C.

[1255] [α]_(D) ²⁶: −11.2° (C=0.5, MeOH)

[1256] IR (KNr):2729, 2625, 2472, 1454, 1356, 1313, 1109, 1061 cm⁻¹

[1257] NMR (DMSO-d₆, δ): 0.93 (3H, t, J=7.5Hz), 1.40-1.78 (2H, m),2.90-3.54 (4H, m), 3.60-4.04 (3H, m), 9.57 (2H, br s)

[1258] MASS (APCI): 116 (M+H)⁺ (free)

PREPARATION 65

[1259] A mixture of 7-oxa-4-azaspiro[2.5]octane hydrochloride (200 mg),2-bromoethanol (0.28 ml) and potassium carbonate (550 mg) inN,N-dimethylformamide (2 ml) was stirred at 90° C. for 48 hours andcooled. The mixture was poured into brine and extracted withdichloromethane. The extract was dried over magnesium sulfate andevaporated under reduced pressure, and purified by column chromatographyon sliica gel using a mixture of methanol and chloroform (2:98) to give4-(2-hydroxyethyl)-7-oxa-4-azaspiro[2.5]octane as an oil. This oil wasdissolved in ethyl acetate (5 ml) and the solution was addedmethanesulfonyl chloride (0.16 ml) and triethylamine (0.3 ml). After 30minutes of stirring at room temperature, the mixture was filtered,evaporated, and purified by column chromatography on silica gel using amixture of ethyl acetate and n-hexane (20:80-30:70) to give4-(2-chloroethyl)-7-oxa-4-azapiro[2.5]octane (1.40 mg) as an oil.

[1260] NMR (CDCl₃, δ): 0.61-0.67 (2H, m), 0.95-1.05 (2H, m), 3.10-3.15(2H, m), 3.22 (2H, t, J=6.9Hz), 3.50 (2H, br s), 3.54-3.64 (2H, m), 3.80(2H, t, J=4.7Hz)

[1261] MASS (APCI): 176 (M+H)⁺

PREPARATION 66

[1262] A mixture of (3R)-3-ethylmorpholine hydrochloride (0.2 g),1,4-dichloro-2-butyne (0.5 ml) and potassium carbonate (0.71 g) inN,N-dimethylformeamide (10 ml) was stirred at room temperature for 2hours. After removal of the solvent, ethyl acetate and sodium hydrogencarbonate solution were added thereto. The organic layer was separatedand the aqueous layer was extracted with ethyl acetate twice. Thecombined organic layer was dried over magnesium sulfate and evaporatedin vacuo. The residue was purified by column chromatography on silicagel with a mixture of ethyl acetate and n-hexane (1:1) as an eluent togive (3R)-4-(4-chloro-2-butynyl)-3-ethylmorpholine (0.2 g) as an oil.

[1263] NMR (CDCl₃, δ): 0.89 (3H, t, J=7.5Hz), 1.20-1.74 (2H, m), 2.42-284 (3H, m), 3.20-3.90 (6H, m), 4.18 (2H, t, J=2.0Hz)

[1264] MASS (APCI): 202 (M+H)⁺

PREPARATION 67

[1265] (1) A mixture of (3S)-3,5-dimethylmorpholine hydrochloride (8.3g), di-tert-butyl dicarbonate (14.34 g) and sodium hydroxide (5.48 g) inwater (30 ml) were stirred at room temperature overnight. Water (50 ml)and isopropyl ether were added to the mixture and the organic layer wasseparated, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel with amixture of ethyl acetate and n-hexane (1:9) as an eluent to give(3S,5S)-4-tert-butoxycarbonyl-3,5-dimethylmorpholine (3.55 g) andmeso-4-tert-butoxycarbonyl-3,5-dimethylmorpholine (2.84 g) (the formerwas less polar) (3S, 5S)-4-tert-Butoxycarbonyl-3,5-dimethylmorpholine(3.55 g) was dissolved in a mixture of dichloromethane (20 ml) andtrifluoroacetic acid (20 ml) and the mixture was stirred at roomtemperature for 2 hours. After removal of the solvent under reducedpressure, 1N sodium hydroxide solution (20 ml) and dichoromethane wereadded thereto. The organic phase was separated, dried over magnesiumsulfate, and was added 4N hydrogen chloride in ethyl acetate (20 ml).The mixture was evaporated in vacuo and the residue was triturated witha mixture of dichloromethane and isopropyl ether to give(3S,5S)-3,5-dimethylmorpholine hydrochloride (1.56 g) as a white solid.

[1266] mp: 172-173° C.

[1267] [α]_(D) ²⁶: +16.370 (C=0.333, MeOH)

[1268] IR (KBr): 3049, 2993, 2978, 2970, 2935, 2916, 2873, 2829, 2817,2800, 2785, 2742, 2723, 1460, 1433, 1385, 1136, 1107, 1028 cm⁻¹

[1269] NMR (CDCl₃, δ): 1.50 (6H, d, J=6.5Hz), 3.44-4.08 (6H, m), 9.97(2H, br s)

[1270] MASS (APCI): 116 (M+H)⁺ (free)

[1271] meso-3,5-Dimethylmorpholine hydrochloride (2.84 g) was preparedfrom meso-4-tert-butoxycarbonyl-3,5-dimethylmorpholine in a similarmanner to the preparation of (3S,5S)-3,5-dimethylmorpholinehydrochloride (1.84 g)

[1272] mp: 85-90° C.

[1273] IR (KBr): 2981, 2945, 2929, 2873, 2860, 2808, 2802, 2773, 2748,2735, 2727, 1672, 1624, 1205, 1182, 1138, 1117, 1057 cm⁻¹

[1274] NMR (CDCl₃, δ) 1.35 (6H, d, J=6.6Hz), 3.22-4.00 (6H, m), 9.44(1H, br s), 10.22 (1H, br s)

[1275] MASS (APCI): 116 (M+H)⁺ (free)

[1276] (2) The following compound was obtained according to a similarmanner to that of Preparation 66.

[1277] (3S,5S)-4-(4-Chloro-2-butynyl)-3,5-dimethylmorpholine

[1278] NMR (CDCl₃, δ): 1.06 (6H, d, J=6.5Hz), 2.95-3.14 (2H, m),3.34-3.54 (4H, m), 3.72 (2H, dd, J=11.0, 3.1Hz), 4.16 (2H, t, J=2.1Hz)

[1279] MASS (APCI): 202 (M+H)⁺

PREPARATION 68

[1280] (1) The following compound was obtained according to a similarmanner to that of Preparation 65.

[1281] 2-(3,3-Dimethylmorpholin-4-yl)ethanol

[1282] NMR (DMSO-d₆, δ): 0.91 (6H, s), 2.3 (2H, t, J=6.7Hz), 2.4-2.5(2H, m), 3.19 (2H, s), 3.3-3.4 (2H, m), 3.5-3.6 (2H, m), 4.27 (1H, t,J=5.4Hz)

[1283] MASS (APCI): 160 (M+H)⁺

[1284] (2) The following compound was obtained according to a similarmanner to that of Preparation 65.

[1285] 2-(3,3-Dimethylmorpholin-4-yl)ethyl methanesulfonate

[1286] The compound was used to the next step without furtherpurification.

PREPARATION 69

[1287] The following compound was obtained according to a similar mannerto that of Preparation 62-(2).

[1288] 4-(3-Chloropropyl)-3,3-dimethylmorpholine

[1289] NMR (DMSO-d₆, δ): 0.92 (6H, s), 1.77 (2H, qui, J=6.4Hz), 2.3-2.5(4H, m), 3.19 (2H, s), 3.55-3.60 (2H, m), 3.67 (2H, t, J=6.4Hz)

[1290] MASS (APCI): 192 (M+H)⁺

PREPARATION 70

[1291] (1) The following compound was obtained according to a similarmanner to that of Preparation 53-(5) starting from(3R)-1-benzyl-3-[(1H-indol-3-yl)methyl]piperazine.

[1292] (2R)-4-Benzyl-1-tert-butoxycarbonyl-2-[(1H-indol-3-yl)-methyl]piperazine

[1293] mp: 143-145° C.

[1294] IR (KBr): 3305, 2976, 2922, 2810, 1664, 1454, 1425, 1367, 1336,1299, 1261, 1223 cm⁻¹

[1295] NMR (DMSO-d₆, δ): 1.00-1.50 (9H, m), 1.80-2.10 (2H, m), 2.60-4.30(9H, m), 6.80-7.70 (10H, m), 10.72 (1H, br s)

[1296] MASS (APCI): 406 (M+H)⁺

[1297] (2) The following compound was obtained according to a similarmanner to that of Preparation 33.

[1298] (2R)-1-tert-Butoxycarbonyl-2-[(1H-indol-3-yl)methyl]-piperazine

[1299] IR (KBr): 3410, 3311, 2976, 2924, 1672, 1454, 1417, 1365, 1259cm⁻¹

[1300] NMR (DMSO-d₆, δ): 1.22 (9H, br s), 2.25-4.20 (10H, m), 6.88-7.70(5H, m) 10.78 (1H, br s)

[1301] MASS (APCI): 316 (M+H)⁺

[1302] (3) The following compound was obtained according to a similarmanner to that of Preparation 34.

[1303] (2R)-1-tert-Butoxycarbonyl-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]-piperazine

[1304] IR (KBr): 3500-3300, 2972, 2935, 1687, 1456, 1417, 1365, 1333,1227 cm⁻¹

[1305] NMR (DMSO-d₆, δ): 0.94 (6H, s), 1.21 (9H, s), 1.82-2.20 (2H, m),2.50-4.30 (17H, m), 6.85-7.66 (5H, m), 10.81 (1H, br s)

[1306] MASS (APCI): 481 (M+H)⁺

[1307] (4) The following compound was obtained according to a similarmanner to that of Preparation 35.

[1308](3-R)-1-[4-(3,3-Dimethylmorpholino)-2-butynyl]-3-[1H-indol-3-yl)methyl]piperazinetrihydrochrolide

[1309] mp: 209-230° C.

[1310] [α]_(D) ²⁶: −10.9° (C=0.5, MeOH)

[1311] IR (KBr): 3600-3300, 2900, 2700-2400, 1645, 1628, 1539, 1516,1454, 1429, 1344 cm⁻¹

[1312] NMR (DMSO-d₆, δ): 1.20-150 (6H, m), 3.10-4.42 (20H, m), 6.95-7.80(5H, m), 9.90-10.25 (2H, m), 11.15 (1H, br s), 11.90 (1H, br s)

[1313] MASS (APCI): 381 (M+H)⁺ (free)

PREPARATION 71

[1314] (1) Acetic acid (5.4 ml) was added to a solution of2-amino-2-methyl-1-propanol (8.4 g) and benzaldehyde (10 g) in1,2-dichloroethane (140 ml) under ice-cooling. After 30 minutes ofstirring at the same temperature, sodium triacetoxyborohydride (26 g)was added by small portions to the solution over 10 minutes. After 2hours of stirring at room temperature, the mixture was poured into asolution of sodium hydrogen carbonate (48 g) in water (300 ml). Theaqueous layer was separated and adjuster to pH 12 with 24% sodiumhydroxide aqueous solution. The alkaline solution was extracted withethyl acetate 12 times. The extract was dried over sodium sulfate andevaporated under reduced pressure to give colorless crystals of2-benzylamino-2-methyl-1-propanol (13.2 g).

[1315] mp: 46.0-47.0° C.

[1316] IR (Nujol): 3330, 3100, 2900, 1450, 1380, 1355 cm⁻¹

[1317] NMR (DMSO-d₆, δ): 0.99 (6H, s), 3.23 (2H, d, J=3.9Hz), 3.62 (2H,s), 4.50-4.60 (1H, m), 7.16-7.36 (5H, m)

[1318] MASS (APCI): 180 (M+H)⁺

[1319] (2) 2-Benzylamino-2-methyl-1-propanol (6.0 g) and potassiumcarbonate (6.95 g) were dissolved in a mixture of dichloromethane (30ml) and water (30 ml) under ice-cooling. Chloroacetyl chloride (2.95 ml)was added to the mixture over 25 minutes and the whole was stirred for 2hours at room temperature. The organic layer was separated, washed withdiluted hydrochloric acid and brine successively, dried over magnesiumsulfate and evaporated under reduced pressure. The residue was dissolvedinto tert-butyl alcohol (40 ml) and potassium tert-butoxide (3.76 g) wasadded to the solution. The whole was stirred for 4 hours under refluxunder nitrogen atmosphere. After cooling to room temperature, theinsoluble mass was filtered off and washed with ethyl acetate. Thefiltrate and washing were combined and the whole was washed with dilutedhydrochloric acid and brine successively, dried over magnesium sulfateand evaporated under reduced pressure. The residue was triturated with amixture of hexane and diisopropyl ether (1:1) and the resulting crystalswere collected by filtration and washed with a mixed solvent of hexaneand diisopropyl ether (1:1) to give colorless crystals of4-benzylamino-5,5-dimethyl-3-morpholinone (4.53 g)

[1320] mp: 76-77° C.

[1321] IR (Nujol): 1635, 1600, 1490, 1460, 1380, 1355 cm⁻¹

[1322] NMR (CDCl₃, δ): 1.20 (6H, s), 3.61 (2H, s), 4.32 (2H, s), 4.64(2H, s), 7.18-7.36 (5H, m)

[1323] MASS (APCI): 220 (M+H)⁺

[1324] (3) 4-Benzyl-5,5-dimethyl-3-morpholinone (4.45 g) was added to anice-cooled suspension of lithium aluminum hydride (0.77 g) in driedtetrahydrofuran (20 ml) under nitrogen atmosphere. After 5 hours ofstirring at 50° C., the reaction mixture was cooled below 5° C., andwater (0.36 ml), 12% sodium hydroxide aqueous solution (0.36 ml) andwater (1 ml) were added thereto successively. After 30 minutes ofstirring, the mixture was filtrated through Celite® pad, and the pad waswashed with ethyl acetate. The filtrate and washing were combined andthe whole was dried over magnesium sulfate, and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel using a mixture of n-hexane and ethyl acetate. The fractionscontaining the objective compound were collected and evaporated underreduced pressure to give 4-benzyl-3,3-dimethylmorpholine as an oil. Theobtained oil and ammonium formate (5.7 g) were dissolved into a mixedsolvent of ethanol (35 ml) and water (5 ml), and the whole was stirredunder reflux for 1 hour under nitrogen atmosphere. After cooling, themixture was filtrated through Celite® pad. The filtrate was evaporatedunder reduced pressure. The residue was dissolved into methanol and 4Nhydrogen chloride in ethyl acetate solution was added thereto. The wholemixture was evaporated and the residue was triturated with a mixture ofethanol and n-hexane (1:1). The resulting crystals were collected byfiltration and washed with a mixed solvent of ethanol and n-hexane (1:1)to give colorless crystals of 3,3-dimethylmorpholine hydrochloride (1.56g).

[1325] mp: 196-197° C.

[1326] IR (Nujol): 3300, 2750, 2650, 2500, 1590, 1460 cm⁻¹

[1327] NMR (DMSO-d₆, δ): 1.21 (6H, s), 3.05-3.11 (2H, m), 3.51 (2H, s),3.76-3.81 (2H, m), 9.66 (2H, br s)

EXAMPLE 66

[1328] Paraformaldehyde (30 mg) and copper(I) iodide (9 mg) were addedto a mixture of(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)piperazine(0.16 g), (3S)-3-ethoxycarbonyl-4-(2-propynyl)morpholine (0.08 g) andN,N-diisopropylethylamine (0.09 ml) in 1,4-dioxane (10 ml) and the wholewas stirred at room temperature for 30 minutes, and then heated at 90°C. for 30 minutes. After cooling, ethyl acetate and sodium hydrogencarbonate solution were added to the mixture. The organic layer wasseparated, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel with amixture of ethyl acetate and n-hexane (1:1) as an eluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoly]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-ethoxycarbonylmorpholino)-2-butynyl]piperazine(0.21 g).

[1329] NMR (CDCl₃, δ): 1.20-5.30 (31H, m), 6.55-7.90 (6H, m)

[1330] MASS (APCI): 654 (M+H)⁺

EXAMPLE 67

[1331] The following compound was obtained according to a similar mannerto that of Example 66.

[1332](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-[(3R)-(4-tert-butoxycarbonyl)morpholin-3-yl]-2-propynyl]piperazine

[1333] NMR (DMSO-d₆, δ): 1.39 (9H, s), 2.09-2.17 (6H, m), 2.30-5.00(18H, m), 6.60-8.15 (6H, m)

[1334] MASS (APCI): 668 (M+H)⁺ (free)

EXAMPLE 68

[1335] To a solution of(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-[(3R)-(4-tert-butoxycarbonyl)morpholin-3-yl]-2-propynyl]piperazine(1.607 g) in ethyl acetate (16 ml) was added hydrogen chloride (4N inethyl acetate, 3 ml). After 8 hours of stirring at room temperature, themixture was evaporated under reduced pressure to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-[(3R)-morpholin-3-yl]-2-propynyl]-piperazinedihydrochloride (1.43 g) as a solid.

[1336] mp: 190-191° C.

[1337] [α]_(D) ²⁷: −14.0° (C=0.5, MeOH)

[1338] IR (KBr): 2927, 1643 cm⁻¹

[1339] NMR (DMSO-d₆, δ): 2.10-2.18 (6H, m), 2.80-5.25 (18H, m),6.65-8.25 (6H, m)

[1340] MASS (APCI): 568 (M+H)⁺ (free)

EXAMPLE 69

[1341] Paraformaldehyde (0.034 g) and copper(I) iodide (12 mg) wereadded to a mixture of(2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-propynyl)piperazine (0.21 g), (3S)-3-methoxymethylmorpholine (0.09g) and N,N-diisopropylethylamine (0.1 ml) in 1,4-dioxane (5 ml) and thewhole was stirred at room temperature for 30 minutes and then heated at70° C. for 2.5 hours. After cooling, ethyl acetate and sodium hydrogencarbonate solution were added to the mixture. The organic layer wasseparated, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel with 3% ofmethanol in chloroform as an eluent to give(2R)-1-[3,5-bis-(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-methoxymethylmorpholino)-2-butynyl]piperazine.It was dissolved in ethyl acetate and the solution was added 4N hydrogenchloride in ethyl acetate. The mixture was evaporated in vacuo and theresidue was triturated with a mixture of ethyl acetate and isopropylether to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-methoxymethylmorpholino)-2-butynyl]piperazinedihydrochloride (0.16 g).

[1342] mp: 60-70° C.

[1343] [α]_(D) ²⁸: −1.8° (C=0.25, MeOH)

[1344] IR (KBr): 1684, 1645, 1512, 1460, 1448, 1431, 1371, 1365, 1325,1281, 1184, 1136, 1072 cm⁻¹

[1345] NMR (DMSO-d₆, δ): 2.00-2.28 (6H, m), 2.60-5.30 (25H, m),6.60-8.30 (6H, m)

[1346] MASS (APCI): 626 (M+H)⁺ (free)

EXAMPLE 70

[1347] The following compounds were obtained according to a similarmanner to that of Example 69.

[1348] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3R)-3-fluoromethylmorpholino)-2-butynyl]piperazinedihydrochloride

[1349] mp: 118-128° C. [α]_(D) ²⁸: −6.8° (C=0.25, MeOH)

[1350] IR (KBr): 1645, 1502, 1435, 1365, 1321, 1282, 1182, 1136, 1049cm⁻¹

[1351] NMR (DMSO-d₆, δ): 2.00-2.30 (6H, m), 2.60-5.30 (22H, m),6.60-8.30 (6H, m)

[1352] MASS (APCI): 614 (M+H)⁺ (free)

[1353] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(tetrahydro-6-fluoro-1,4-oxazepin-4(5H)-yl)-2-butynyl]piperazinedihydrochloride

[1354] mp: 90-100° C.

[1355] [α]_(D) ²⁸: +1.60 (C=0.25, MeOH)

[1356] IR (KBr): 1645, 1504, 1433, 1373 1365, 1323, 1282, 1219, 1182,1136 cm⁻¹

[1357] NMR (DMSO-d₆, δ): 2.00-2.30 (6H, m), 2.60-5.30 (22H, m),6.60-8.28 (6H, m)

[1358] MASS (APCI): 614 (M+H)⁺ (free)

EXAMPLE 71

[1359] The following compounds were obtained according to a similarmanner to that of Example 31.

[1360] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3-methoxymethyl-3-methylmorpholino)-2-butynyl]piperazinedihydrochloride

[1361] mp: 155-160° C.

[1362] [α]_(D) ²⁵: −11.6° (C=0.25, MeOH)

[1363] IR (KBr): 1645, 1437, 1362, 1323, 1281, 1219, 1182, 1138, 1055cm⁻¹

[1364] NMR (DiSO-d₆, δ): 1.20-1.50 (3H, m), 2.05-2.26 (6H, m), 2.60-5.20(24H, m), 6.60-8.30 (6H, m)

[1365] MASS (APCI): 640 (M+H)⁺ (free)

[1366] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-ethoxymethylmorpholino)-2-butbutynyl]piperazinedihydrochloride

[1367] mp:155-160° C.

[1368] [α]_(D) ²⁵: +0.6° (C=0.25, MeOH)

[1369] IR (KBr):1645, 1439, 1371, 1281, 1217, 1182, 1136, 1072, 1032cm⁻¹

[1370] NMR (DM4SO-d₆, δ): 1.13 (3H, t, J=7.0Hz), 2.02-5.24 (30H, m),6.60-8.28 (6H, m)

[1371] MASS (APCI): 640 (M+H)⁺ (Free)

[1372] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S,5S)-3,5-dimethylmorpholino)-2-butynyl]piperazine dihydrochloride

[1373] mp: 160-165° C.

[1374] [α]_(D) ²⁶+14.2° (C=0.25, MeOH)

[1375] IR (KBr): 1657, 1649, 1643, 1433, 1356, 1281, 1186, 1136, 1109cm⁻¹

[1376] NMR (DMSO-d₆l 5): 1.10-1.45 (6H, m), 2.00-2.28 (6H, m), 2.60-5.20(19H, m), 6.60-8.28 (6H, m)

[1377] MASS (APCI): 610 (M+H)⁺ (free)

[1378] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-hydroxymethylmorpholino)-2-butynyl]piperazinedihydrochloride

[1379] mp: 130-150° C.

[1380] [α]_(D) ²⁸−2.6° (C=0.25, MeOH)

[1381] IR (KBr): 1691, 1645, 1512, 1458, 1442, 1433, 1371, 1365, 1325,1281, 1217, 1182, 1136, 1059 cm⁻¹

[1382] NMR (DMSO-d₆, δ): 2.00-2.30 (6H, m), 2.60-5.30 (22H, m),6.60-8.28 (6H, m)

[1383] MASS (APCI): 612 (M+H)⁺ (free)

[1384] (5)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((2S)-2-methoxymethylmorpholino)-2-butynyl]piperazinedihydrochloride

[1385] mp: 85-95° C.

[1386] [α]_(D) ²⁵: −4.71 (C=0.255, MeOH)

[1387] IR (KBr): 1641, 1631, 1442, 1281, 1134 cm⁻¹

[1388] NMR (DMSO-d₆, δ): 2.00-2.30 (6H, m), 2.60-5.28 (25H, m),6.60-8.30 (6H, m)

[1389] MASS (APCI): 626 (M+H)⁺ (free)

[1390] (6)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzy)-4-[4-((2R)-2-methoxymethylmorpholino)-2-butynyl]piperazinedihydrochloride

[1391] mp: 80-90° C.

[1392] [α]_(D) ²⁵: −15.00° (C=0.24, MeOH)

[1393] IR (KBr): 1657, 1649, 1641, 1631, 1441, 1431, 1281, 1186, 1176,1136, 1109 cm⁻¹

[1394] NMR (DMSO-d₆, δ): 2.00-2.30 (6H, m), 2.60-5.20 (25H, m),6.60-8.30 (6H, m)

[1395] MASS (APCI): 626 (M+H)⁺ (free)

[1396] (7)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-4-((3R)-3-methoxymethyl-morpholino)-2-butenyl]piperazinedihydrochloride

[1397] mp: 240-250° C.

[1398] [α]_(D) ²⁸: −19.47° (C=0.19, MeOH)

[1399] IR (KBr): 1647, 1635, 1618, 1456, 1435, 1379, 1281, 1186, 1132,1108 cm⁻¹

[1400] NMR (DMSO-d₆, δ): 2.00-2.28 (6H, m), 2.60-5.20 (25H, m),5.80-8.30 (8H, m)

[1401] MASS (APCI): 628 (M+H)⁺ (free)

EXAMPLE 72

[1402] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-chloro-2-butynyl]piperazine(1.2 g) and (3S)-3-ethoxycarbonylmorpholine hydrochloride (0.43 g),potassium carbonate (1.09 g) and a trace of potassium iodide inN,N-dimethylformamide (50 ml) was stirred at 55° C. for 12 hours. Aftercooling, the solvent was removed by evaporation, and ethyl acetate andwater were added thereto. The organic layer was separated, dried overmagnesium sulfate, and evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel with a mixture of ethyl acetate andn-hexane (2:3) as an eluent to give(2R)-1-[3,5-bis(trifluoromethylbenzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-ethoxycarbonylmorpholino)-2-butynyl]piperazine(0.29 g) as an oil.

[1403] NMR (CDCl₃, δ): 1.20-5.30 (31H, m), 6.55-7.90 (6H, m)

[1404] MASS (APCI): 654 (M+H)⁺

EXAMPLE 73

[1405] The following compounds were obtained according to a similarmanner to that of Example 72.

[1406] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3R)-3-ethylmorpholino)-2-butynyl]piperazinedihydrochloride

[1407] [α]_(D) ²⁷: −22.7° (C=0.5, MeOH)

[1408] IR (KBr): 3600, 1645, 1460, 1280, 1180, 1135 cm⁻¹

[1409] NMR (DMSO-d₆, δ): 0.83-5.17 (31H, m), 6.62-8.24 (6H, m)

[1410] MASS (APCI): 610 (M+H)⁺ (free)

[1411] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3-ethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]-piperazinedihydrochloride

[1412] [α]_(D) ²⁸: +11.20 (C=0.5, MeOH)

[1413] IR (KBr): 3365, 2600, 1645, 1430, 1280, 1180, 1135 cm⁻¹

[1414] NMR (DMSO-d₆, δ): 0.67-5.20 (25H, m), 6.60-8.28 (8H, m), 10.96(1H, s)

[1415] MASS (APCI): 621 (M+H)⁺ (free)

[1416] (3) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-4-((3S)-3-methoxymethylmorpholino)-2-butenyl]piperazinedihydrochloride

[1417] mp: 130-140° C.

[1418] [α]_(D) ²⁷: +2.0° (C=0.25, MeOH)

[1419] IR (KBr): 1653, 1647, 1637, 1282, 1188, 1134 cm⁻¹

[1420] NMR (DMSO-d₆, δ): 2.00-2.28 (6H, m), 2.70-5.28 (25H, m),6.00-8.32 (8H, m)

[1421] MASS (APCI): 628 (M+H)⁺ (free)

EXAMPLE 74

[1422] A solution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-ethoxycarbonylmorpholino)-2-butynyl]piperazine(0.42 g) in ethanol (30 ml) was added 1N sodium hydroxide solution (30ml) and the whole was stirred at room temperature for 2 hours. Thesolvent was removed under reduced pressure and the residual aqueoussolution was neutralized with conc. hydrochloric acid. The solution wasextracted with dichloromethane. The extract was dried over magnesiumsulfate and evaporated in vacuo to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-carboxymorcholino)-2-butynyl]piperazine(0.26 g) as an oil.

[1423] NMR (CDCI₆, δ): 2.00-5.28 (26H, m), 6.50-7.90 (6H, m)

[1424] MASS (APCI):626 (M+H)⁺

EXAMPLE 75

[1425] A tetrahydrofuran solution of dimethylamine (2 M, 0.32 ml) wasadded to a mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-carboxymorpholino)-2-butynyl]piperazine (0.13 g),1-hydroxybenzotriazole (85 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g) inN,N-dimethylformamide (5 ml), and the whole was stirred at roomtemperature for 5 hours. After the solvent was removed by evaporation,dichloromethane and sodium hydrogen carbonate solution were added to theresidue. The oraanic layer was separated, dried over magnesium sulfate,and evaporated in vacuo. The residue was purified by columnchromatography on silica gel with 3% of methanol in dichloromethane asan eluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-dimethylcarbamoylmorpholino)-2-butynyl]piperazine.It was dissolved in ethyl acetate (10 ml) and the solution was added 4Nhydrogen chloride in ethyl acetate (0.26 ml). The mixture was evaporatedin vacuo and the residue was triturated with a mixture of ethyl acetateand isopropyl ether to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-dimethylcarbamoylmorpholino)-2-butyny]piperazined-hydrochloride (0.12 g) as a solid.

[1426] mp: 150-160° C.

[1427] [α]_(D) ²⁷: −33.2° (C=0.25, MeOH)

[1428] IR (KBr): 1653, 1506, 1433, 1371, 1325, 1281, 1182 1136, 1063,1026 cm⁻¹

[1429] NMR (DMSO-d₆, δ): 2.00-2.30 (6H, m), 2.60-5.20 (26H, m),6.60-8.30 (6H, m)

[1430] MASS (APCI): 653 (M+H)⁺ (free)

EXAMPLE 76

[1431] The following compounds were obtained according to a similarmanner to that of Example 5.

[1432] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-(3-[2-(4-methoxy)pyridyl]-2-propynyl)-piperazinedihydrochloride

[1433] mp: 130-135° C.

[1434] [α]_(D) ²⁸: −2.8° (C=0.5, MeOH)

[1435] IR (KBr): 3600, 3314, 1640, 1625, 1430, 1280, 1180, 1135 cm⁻¹

[1436] NMR (DMSO-d₆, δ): 3.95 (3H, s), 2.74-5.24 (11H, m), 6.60-8.60(11H, m), 10.92 (1H, s)

[1437] MASS (APCI): 601 (M+H)⁺ (free)

[1438] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-{3-[2-(4-methoxy)pyridyl-]-2-propynyl}-piperazine dihydrochloride

[1439] mp: 95-100° C.

[1440] [α]_(D) ²⁸: −6.2° (C=0.5, MeOH)

[1441] IR (KBr): 3405, 2930, 2590, 1625, 1430, 1280, 1180, 1135 cm⁻¹

[1442] NMR (DMSO-d₆, δ): 2.51 (3H, s), 2.03-5.20 (17H, m), 6.66-8.66(9H, m)

[1443] MASS (APCI): 590 (M+H)⁺ (free)

[1444] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-{3-[2-(4-methyl)pyridyl]-2-propynyl}-piperazinedihydrochloride

[1445] mp: 150-155° C.

[1446] [α]_(D) ²⁷: −3.3° (C=0.5, MeOH)

[1447] IR (KBr): 3335, 1645, 1498, 1430, 1280, 1185 cm⁻¹

[1448] NMR (DMSO-d₆, δ): 2.37 (3H, s), 2.10-5.24 (11H, m), 6.60-8.67(11H, m), 10.93 (1H, s)

[1449] MASS (APCI): 585 (M+H)⁺ (free)

[1450] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-{3-[2-(4-methoxycarbonyl)pyridyl]-2-propynyl}piperazinedihydrochloride

[1451] mp: 125-130° C.

[1452] [α]_(D) ²⁸: −30.3° (C=0.5, MeOH)

[1453] IR (KBr): 2600, 1740, 1645, 1430, 1280, 1180 cm⁻¹

[1454] NMR (DMSO-d₆, δ): 3.93 (3H, s), 2.00-5.20 (17H, m), 6.60-8.90(9H, m)

[1455] MASS (APCI): 618 (M+H)⁺ (free)

EXAMPLE 77

[1456] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]piperazine(0.20 g), (3S,5S)-3,5-dimethyl-4-(4-chloro-2-butynyl)morpholine (0.11 g)and potassium carbonate (0.31 g) in N,N-dimethylformamide (4 ml) wasstirred at 60° C. for 3 hours. After cooling, the solvent was removedunder reduced pressure and the residue was partitioned between ethylacetate and sodium hydrogen carbonate solution. The organic layer wasseparated, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel with 3% ofmethanol in ethyl acetate as an eluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S,5S)-3,5-dimethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]-piperazine.It was dissolved in ethyl acetate and the solution was added 4N hydrogenchloride in ethyl acetate. The mixture was evaporated in vacuo and theresidue was triturated with isopropyl ether to give(2R)-1-[3,5-bis-(trifluoromethyl)benzoyl]-4-[4-((3S,5S)-3.5-dimethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]-piperazinedihydrochioride (0.11 g).

[1457] mp: 170-180° C.

[1458] [α]_(D) ²⁷: +21.570 (C=0.255, MeOH)

[1459] IR (KBr): 1645, 1637, 1458, 1431, 1360, 1281, 1184, 1136, 1111cm⁻¹

[1460] NMR (DMSO-d₆, δ): 1.10-1.45 (6H, m), 2.70-5.30 (19H, m),6.60-8.28 (8H, m)

[1461] MASS (APCI): 621 (M+H)⁺ (free)

EXAMPLE 78

[1462] The following compounds were obtained according to a similarmanner to that of Example 77.

[1463] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl-]4-[4-((3R)-3-ethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]-piperazinedihydrochloride

[1464] mp: 176-180° C.

[1465] [α]_(D) ²⁶: −12.2° (C=0.25, MeOH)

[1466] IR (KBr): 1635, 1454, 1437, 1358, 1333, 1281, 1223, 1182, 1138,1068 cm⁻¹

[1467] NMR (DMSO-d₆, δ): 0.68-5.30 (25H, m), 6.55-8.30 (8H, m), 10.95(1H, s)

[1468] MASS (APCI):621 (M+H)⁺ (free)

[1469] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[3-(3,3-dimethylmorpholino)propyl]-2-[(1H-indol-3-yl)methyl]-piperazinedihydrochloride

[1470] mp: 107˜° C.

[1471] [α]_(D) ²⁷: −7.0° (C=0.5, MeOH)

[1472] IR (Kr) 3500-3400, 2933, 2599, 1645, 1637, 1458, 1435, 1362, 1280cm⁻¹

[1473] NMR (DMSO-d₆, δ): 1.2-1.4 (6H, m), 2.1-1.6 (2H, m), 2.7-5.2 (19H,m), 6.6-8.3 (8H, m), 10.9-11.8 (3H, m)

[1474] MASS (APCI): 611 (M+H)⁺ (free)

[1475] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-{2-[7-oxa-4-azaspiro[2.5]octan-4-yl]-ethyl}}piperazinedihydrochloride

[1476] mp: 110-113° C.

[1477] [α]_(D) ²⁸: −13.8° (C=0.5, MeOH)

[1478] IR (KBr): 3435, 1645 cm⁻¹

[1479] NMR (DMSO-d₆, δ): 0.80-0.95 (2H, m), 1.20-1.50 (2H, m), 2.11-2.19(6H, m), 3.00-5.15 (19H_(,) m), 6.65-8.17 (6H, m)

[1480] MASS (APCI): 584 (M+H)⁺ (free)

[1481] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(3,3-dimethylmorpholino)propyl]-piperazinedihydrochloride

[1482] mp: 197° C.

[1483] [α]_(D) ²⁷: −17.8° (C=0.5, MeOH)

[1484] IR (KBr): 3500-3400, 2933, 2692, 1645, 1637, 1456, 1430, 1435,1280 cm⁻¹

[1485] NMR (DMSO-d₆, δ): 1.33 (6H, s), 1.92-5.2 (27H, m), 6.6-8.3 (6H,m), 11.0-11.5 (2H, m)

[1486] MASS (APCI): 600 (M+H)⁺ (free)

EXAMPLE 79

[1487] The following compounds were obtained according to a similarmanner to that of Example 5.

[1488] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(3,3-dimethylmorpholino)ethyl]-2-[(1H-indol-3-yl)methyl]-piperazinedihydrochloride

[1489] mp: 247-258° C.

[1490] [α]_(D) ²⁷: −4.5° (C=0.5, MeOH)

[1491] IR (KBr): 3500-3400, 1645, 1637, 1280 cm⁻¹

[1492] NMR (DMSO-d₆, δ): 1.2-1.5 (6H, m), 2.8-5.3 (19H, m), 6.6-8.3 (8H,m), 11.0 (1H, br s), 11.5-12.1 (2H, m)

[1493] MASS (APCI): 597 (M+H)⁺ (free)

[1494] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(3,3-dimethylmorpholino)ethyl]-piperazinedihydrochloride

[1495] mp: 190-210° C.

[1496] [α]27 -13.90 (C=0.5, MeOH)

[1497] IR (KBr): 3500-3400, 1643, 1450, 1430, 1384, 1363, 1280, 1185cm⁻¹

[1498] NMR (DMSO-d₆, δ): 1.40 (6H, s), 2.10-2.2 (6H, m), 2.7-5.2 (19H,m), 6.6-8.2 (6H, m), 11.6-12.2 (2H, m)

[1499] MASS (APCI): 586 (M+H)⁺ (free)

EXAMPLE 80

[1500] The following compounds were obtained according to a similarmanner to that of Example 39.

[1501] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((3R)-3-ethylmorpholino)ethyl]-piperazinedihydrochloride

[1502] [α]_(D) ²⁸: −23.6° (C=0.5, MeOH)

[1503] IR (KBr): 3425, 2600, 1645, 1640, 1280, 1185, 1135 cm⁻¹

[1504] NMR (DMSO-d₆, δ): 0.95 (3H, t, J=7.2Hz), 1.57-5.20 (28H, m),6.66-8.28 (6H, m)

[1505] MASS (APCI): 586 (M+H)⁺ (free)

[1506] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((3S)-3-hydroxymethylmorpholino)-ethyl]piperazinedihydrochloride

[1507] mp: 150-160° C.

[1508] [α]_(D) ²⁶: −8.4° (C=0.25, MeOH)

[1509] IR (KBr): 1643, 1437, 1375, 1323, 1282, 1221, 1184, 1138, 1047cm⁻¹

[1510] NMR (DMSO-d₆, δ): 2.00-2.28 (6H, m), 2.60-5.20 (23H, m),6.58-8.28 (6H, m)

[1511] MASS (APCI): 588 (M+H)⁺ (free)

[1512] (3)(2R)-1-[3,5-Bis(trifluorom-ethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((2S)-2-methoxymethylmorpholino)-ethyl]piperazine dihydrochloride

[1513] mp: 180-190° C.

[1514] [α]_(D) ²⁶: −12.36° (C=0.275, MeOH)

[1515] IR (KBr): 1653, 1647, 1635, 1282, 1182, 1136 cm⁻¹

[1516] NMR (DMSO-d₆, δ): 2.00-5.20 (31H, m), 6.60-8.30 (6H, m)

[1517] MASS (APCI): 602 (M+H)⁺ (free)

[1518] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((3S)-3-methoxymethylmorpholino)-ethyl]piperazinedihydrochloride

[1519] mp: 90-100° C.

[1520] [α]_(D) ²⁷: −9.80 (C=0.25, MeOH)

[1521] IR (KBr): 1645, 1512, 1506, 1460, 1433, 1371, 1325, 1282, 1223,1184, 1136, 1053 cm⁻¹

[1522] NMR (DMSO-d₆, δ): 2.00-2.30 (6H, m), 2.60-5.20 (25H, m),6.60-8.40 (6H, m)

[1523] MASS (APCI): 602 (M+H)⁺ (free)

[1524] (5)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(2-methoxyymnethylmorpholino)ethyl]-piperazinedihydrochloride

[1525] mp: 150-154° C.

[1526] [α]_(D) ²⁸: −5.8° (C=0.5, MeOH)

[1527] IR (KBr): 3463-3406, 1647 cm⁻¹

[1528] NMR (DMSO-d₆, δ): 2.10-2.18 (6H, m), 2.40-5.10 (25H, m),6.55-8.16 (6H, m)

[1529] MASS (APCI): 602 (M+H)⁺ (free)

[1530] (6)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-((3S)-3-methoxymethylmorpholino)-propyl]piperazinedihydrochloride

[1531] mp: 55-60° C.

[1532] [α]_(D) ²⁷: −1.4° (C=0.25, MeOH)

[1533] IR (KBr): 1653, 1647, 1635, 1282, 1182, 1134, 1109 cm⁻¹

[1534] NMR (DMSO-d₆, δ): 1.80-5.22 (33H, m), 6.60-8.30 (6H, m)

[1535] MASS (APCI): 616 (M+H)⁺ (free)

[1536] (7)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(2-methoxymethylmorpholino)propyl]-piperazinehydrochloride

[1537] mp: 145-155° C.

[1538] [α]_(D) ²⁸: −11.9° (C=0.5, MeOH)

[1539] IR (KBr): 3455-3407, 1645 cm⁻¹

[1540] NMR (DMSO-d₆, δ): 2.10-2.19 (6H, m), 2.10-5.10 (27H, m),6.68-8.17 (6H, m)

[1541] MASS (APCI): 616 (M+H)⁺ (free)

[1542] (8)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[2-((3S)-3-methoxymethylmorpholino)ethyl]-piperazinedihydrochloride

[1543] mp: 175-185° C.

[1544] [α]_(D) ²⁷: −0.6° (C=0.25, MeOH)

[1545] IR (KBr): 1645, 1637, 1458, 1431, 1383, 1362, 1281, 1184, 1138,1111 cm⁻¹

[1546] NMR (DMSO-d₆, δ): 2.80-5.28 (25H, m), 6.60-8.30 (8H, m)

[1547] MASS (APCI): 613 (M+H)⁺ (free)

[1548] (9)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[2-((3R)-3-methoxymethylmorpholino)ethyl]-piperazinedihydrochloride

[1549] mp: 130-150° C.

[1550] [α]_(D) ²⁶: −15.8° (C=0.25, MeOH)

[1551] IR (KBr): 1653, 1645, 1635, 1281 cm⁻¹

[1552] NMR (DMSO-d₆, δ): 2.60-5.25 (25H, m), 6.60-8.32 (8H, m), 10.96(1H, s)

[1553] MASS (APCI): 613 (M+H)⁺ (free)

[1554] (10)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-((3R)-3-methoxymethylmorpholino)-propyl]piperazinedihydrochloride

[1555] mp: 80-100° C.

[1556] [α]_(D) ²⁸: −21.59° (C=0.22, MeOH)

[1557] IR (KBr): 1653, 1647, 1637, 1618, 1508, 1473, 1464, 1456, 1448,1435, 1431, 1385, 1373, 1363, 1281, 1215, 1184, 1136, 1109 cm⁻¹

[1558] NMR (DMSO-d₆, δ): 2.00-5.40 (33H, m), 6.55-8.30 (6H, m)

[1559] MASS (APCI): 616 (M+H)⁺ (free)

EXAMPLE 81

[1560] The following compounds were obtained according to a similarmanner to that of Example 37.

[1561] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((3R)-3-fluoromethylmorpholino)-ethyl]piperazinedihydrochloride

[1562] mp: 145-155° C.

[1563] [α]_(D) ²⁶: −19.2° (C=0.25, MeOH)

[1564] IR (KBr): 1643, 1437, 1367, 1321, 1281, 1221, 1184, 1138, 1034cm⁻¹

[1565] NMR (DMSO-d₆, δ): 2.00-2.28 (6H, m), 2.60-5.20 (22H, m),6.60-8.32 (6H, m)

[1566] MASS (APCI): 590 (M+H)⁺ (free)

[1567] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(3-methoxymethyl-3-methylmorpholino)ethyl]piperazinedihydrochloride

[1568] mp: 60-70° C.

[1569] [α]_(D) ²⁷: −15.5° (C=0.3, MeOH)

[1570] IR (KBr): 1643, 1469, 1439, 1375, 1369, 1360, 1323, 1282, 1225,1184, 1138 cm⁻¹

[1571] NMR (DMSO-d₆, δ): 1.10-1.50 (3H, s), 2.00-5.22 (30H, m),6.60-8.30 (6H, m)

[1572] MASS (APCI): 616 (M+H)⁺ (free)

[1573] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((3S)-3-ethoxymethylmorpholino)-ethyl]piperazinedihydrochloride

[1574] mp: 60-65° C.

[1575] [α]_(D) ²⁷: −8.2° (C=0.25, MeOH)

[1576] IR (Kr) 1643, 1437, 1369, 1321, 1281, 1221, 1182, 1138, 1072,1051 cm⁻¹

[1577] NMR (DMSO-d₆, δ): 1.10-1.30 (3H, m), 2.00-5.25 (30H, m),6.60-8.40 (6H, m)

[1578] MASS (APCI): 616 (M+H)⁺ (free)

[1579] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((3R)-3-methoxymethylmorpholino)-ethyl]piperazinedihydrochloride

[1580] mp: 90-100° C.

[1581] [α]_(D) ²⁷: −26.48° (C=0.287, MeOH)

[1582] IR (KBr): 1635, 1469, 1454, 1437, 1375, 1369, 1360, 1321, 1282,1221, 1184, 1136, 1074 cm⁻¹

[1583] NMR (DMSO-d₆, δ): 2.00-5.22 (31H, m), 6.60-8.28 (6H, m)

[1584] MASS (APCI): 602 (M+H)⁺ (free)

[1585] (5)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzy)-4-[2((2R) -2-methoxymethylmorpholino)-ethyl]piperazine dihydrochloride

[1586] mp: 160-170° C.

[1587] [α]_(D) ²⁷: −17.40° (C=0.27, MeOC)

[1588] IR (KBr): 1645, 1454, 1431, 1383, 1363, 1321, 1281, 1215, 1184,1138, 1109 cm⁻¹

[1589] NMR (DMSO-d₆, δ): 2.00-2.28 (6H, m3), 2.60-5.22 (25H, m),6.60-8.28 (6H, m)

[1590] MASS (APCI): 602 (M+H)⁺ (free)

[1591] (6)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[2-((3S)-3-ethylmorpholino)ethyl]-piperazine dihydrochioride

[1592] [α]_(D) ²⁸: −16.2° (C=0.5, MeOH)

[1593] IR (KBr): 3400, 2610, 1430, 1280, 1185, 1135 cm⁻¹

[1594] NMR (DMSO-d₆, δ): 0.86-5.31 (25H, m), 7.00-8.20 (10H, m)

[1595] MASS (APCI): 608 (M+H)⁺ (free)

[1596] (7)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl)-4-[2-((2S)-2-methoxymethylmorpholino)ethyl]-piperazinedihydrochloride

[1597] mp: 160-170° C.

[1598] [α]_(D) ²⁷: −3.0° (C=0.25, MeOH)

[1599] IR (KBr): 1645, 1637, 1618, 1458, 1429, 1362, 1281, 1184, 1138,1109, 1099 c⁻¹

[1600] NMR (DMSO-d₆, δ): 2.60-5.30 (25H, m), 6.60-8.30 (8H, m)

[1601] MASS (ADPC): 613 (M+H)⁻ (free)

[1602] (8)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[2-((2R)-2-methoxymethylmorpholino)ethyl]-piperazinedihydrochloride

[1603] mp: 190-200° C.

[1604] [α]_(D) ²⁷: −15.0° (C=0.24, MeOH)

[1605] IR (KBr): 1641, 1458, 1421, 1362, 1282, 1176, 1130, 1113, 1099,1074 cm⁻¹

[1606] NMR (DMSO-d₆, δ): 2.60-5.28(25H, m), 6.60-8.28 (8H, m), 10.94(1H, s)

[1607] MASS (APCI): 613 (M+H)⁺ (free)

[1608] (9)(2-)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[1H-indol-3-yl)methyl]-4-[2-((3S,5S)-3,5-dimethylmorpholino)ethyl]-piperazine dihydrochloride

[1609] mp: 170-180° C.

[1610] [α]_(D) ²⁷: +13.49° (C=0.315, MeOH)

[1611] IR (KBr): 1645, 1637, 1458, 1448, 1429, 1362, 1281, 1184, 1136,1111 cm⁻¹

[1612] NMR (DMSO-d₆, δ): 1.08-1.50 (6H, m), 2.60-5.20 (19H, m),6.55-8.30 (8H, m)

[1613] MASS (APCI): 597 (M+H)⁺ (free)

[1614] (10)(9?)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-((3R)-3-ethylmorpholino)ethyl]-2-[(1H-indol-3-yl)methyl]-piperazinedihydrochloride

[1615] [α]_(D) ²⁸: −14.9° (C=0.5, MeOH)

[1616] IR (KBr): 3365, 2590, 2470, 1645, 1430, 1280, 1185, 1140 cm⁻¹

[1617] NMR (DMSO-d₆, δ): 1.53-5.20 (25H, m), 6.60-8.28 (8H, m), 10.95(1H, s)

[1618] MASS (APCI): 597 (M+H)⁺ (free)

[1619] (11)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-((3S)-3-ethylmorpholino)ethyl]-2-[(1H-indol-3-yl)methyl]-piperazinedihydrochloride

[1620] [α]_(D) ²⁸: +6.00 (C=0.5, MeOH)

[1621] IR (KBr): 3300, 2670, 2610, 1645, 1430, 1280, 1180, 1140 cm⁻¹

[1622] NMR (DMSO-d₆, δ): 0.84-5.20 (25H, m), 6.64-8.28 (8H, m), 10.94(1H, s)

[1623] MASS (APCI): 597 (M+H)⁻ (free)

EXAMPLE 82

[1624] A solution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-methoxymethylinorpholino)-2-butynyl]piperazine(0.09 g) in methanol (10 ml) was hydrogenated in the presence of 10%palladium-carbon (40 mg) at room remperature. After 1 hour,palladium-carbon was removed by filtration and the filtrate wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel with a mixture of methanol and ethylacetate as an eluent to give(2R)-1-[3,5-bis-(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-methoxymethylmorpholino)butyl]piperazine.It was dissolved in ethyl acetate (10 ml) and 4N hydrogen chloride inethyl acetate (0.5 ml) was added thereto. The mixture was evaporated invacuo and the residue was triturated with a mixture of ethyl acetate andisodropyl ether to give(2R)-1-(3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-methoxymethylmorpholino)butyl]piperazinedihydrochloride (0.03 g) as a solid.

[1625] NMR (DMSO-d₆, δ): 1.60-2.00 (4H, m), 2.00-2.30 (6H, m), 2.60-5.20(25H, m), 6.60-8.30 (6H, m), 10.40-11.60 (2H, m)

[1626] MASS (APCI): 630 (M+H)⁺ (free)

EXAMPLE 83

[1627] The following compounds were obtained according to a similarmanner to that of Example 82.

[1628] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-{3-[2-(4-methoxy)pyridyl]propyl}-piperazinedihydrochloride

[1629] mp: 130-140° C.

[1630] [α]_(D) ²⁸: −10.4° (C=0.5, MeOH)

[1631] IR (KBr): 3425, 2400, 1640, 1500, 1430, 1280, 1180, 1135 cm⁻¹

[1632] NMR (DMSO-d₆, δ): 4.08 (3H, s), 2.05-5.14 (21H, m), 6.60-8.72(9H, m)

[1633] MASS (APCI): 594 (M+H)⁺ (free)

[1634] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-{3-[2-(4-methyl)pyridyl]propyl}piperazinedihydrochloride

[1635] mp: 120-130° C.

[1636] [α]_(D) ²⁷: −5.0° (C=0.5, MeOH)

[1637] IR (KBr): 3420, 1645, 1498, 1430, 1280, 1135 cm⁻¹

[1638] NMR (DMSO-d₆, δ): 2.55 (3H, s), 2.14-5.20 (15H, m), 6.64-8.74(11H, m), 10.95 (1H, s)

[1639] MASS (APCI): 589 (M+H)⁺ (free)

[1640] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-{3-[2-(4-methoxycarbonyl)pyridyl]-propyl}piperazinedihydrochloride

[1641] mp: 115-125° C.

[1642] [α]_(D) ²⁸: −11.7° (C=0.5, MeOH)

[1643] IR (KBr): 2650, 2625, 1740, 1645, 1460, 1280, 1135 cm⁻¹

[1644] NMR (DMSO-d₆, δ): 3.92 (3H, s), 2.07-5.14 (21H, m), 6.00-8.78(9H, m)

[1645] MASS (APCI): 622 (M+H)⁺ (free)

EXAMPLE 84

[1646] To a stirred suspension of 2- (3,4-methylenedioxybenzyl)-piperazine dihydrochloride (104 mg) andpotassium carbonate (196 mg) in N,N-dimethylformamide (4 ml) was added4-(4-chloro-2-butynyl)-3,3-dimethylmorpholine hydrochloride (84.5 mg) at5° C. under nitrogen atmosphere and the mixture was gradually warmed toroom temperature over night. To the above stirred suspension was added3,5-bis(trifluoromethyl)-benzoyl chloride (98.2 mg) at 5° C. and themixture was stirred for 1 hour at this temperature. The mixture wasextracted with ethyl acetate and the extract was washed with water, anddried over magnesium sulfate. The usual work up followed by flashchromatography on silica gel with a mixture of dichloromethane andmethanol (50:1) gave1-[3,5-bis-(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-(3,4-methylenedioxybenzyl)piperazine,which was dissolved in ethyl acetate and treated with 4N hydrogenchloride in ethyl acetate to give1-[3,5-bis-(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-(3,4-methylenedioxybenzyl)piperazinedihydrochloride (107 mg) as a powder.

[1647] NMR (DMSO-d₆, δ): 1.32 (6H, m), 2.20-5.00 (19H, m), 5.96 (2H, s),6.43-8.17 (6H, m)

[1648] MASS (APCI): 626 (M+H)⁺ (free)

EXAMPLE 85

[1649] The following compounds were obtained according to a similarmanner to that of Example 84.

[1650] (1)1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-(4-hydroxymethyl-3-methylbenzyl)piperazinedihydrochloride

[1651] NMR (DMSO-d₆, δ): 1.32-1.38 (6H, m), 2.00-5.22 (25H, m),6.55-8.17 (6H, m)

[1652] MASS (APCI): 626 (M+H)⁺ (free)

[1653] (2)2-[(1,4-Benzodioxan-6-yl)methyl]-1-[3,5-bis-(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazinedihydrochloride

[1654] NMR (DMSO-d₆, δ): 1.21-1.23 (6H, m), 2.62-5.00 (23H, m),6.37-8.48 (6H, m)

[1655] MASS (APCI): 640 (M+H)⁺ (free)

[1656] (3)1-[3,5-Bis(triflucromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-(4-methoxy-3-methylbenzyl)piperazinedihydrochloride

[1657] NMR (DMSO-d₆, δ): 1.33-1.40 (6H, m), 2.00-5.22 (25H, m),6.64-8.15 (6H, m)

[1658] MASS (APCI): 626 (M+H)⁺ (free)

EXAMPLE 86

[1659] To a mixed solution of1-(benzyloxycarbonyl)-3-(2,3-dimethoxybenzyl)piperazine (0.65 g) andtriethylamine (0.293 ml) in dichloromethane (17 ml) was added dropwise asolution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.534 g) indichloromethane (2.5 ml) under ice-cooling. After being stirred at thesame temperature for 2 hours, the reaction mixture was poured into amixed solvent of water (40 ml) and dichloromethane (25 ml) and the wholewas adjusted to pH 9 with aqueous sodium hydrogen carbonate solution.The organic layer was separated, washed with brine, dried over sodiumsulfate and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel (10 g) using a mixed solvent ofn-hexane and ethyl acetate (2:1). The fractions containing the objectivecompound were collected and evaporated under reduced pressure to give1-[3,5-bis(trifluoromethyl)benzoyl]-4-(benzyloxycarbonyl)-2-(2,3-dimethoxybenzyl)piperazine(0.84 g).

[1660] IR (KBr): 1732, 1714, 1705, 1647, 1431, 1281, 1134 cm⁻¹

[1661] NMR (CDCl₃, δ): 2.60-4.70 (9H, m), 3.79 (6H, s), 5.20 (2H, s),6.40-8.60 (11H, m)

[1662] MASS (APCI): 611 (M+H)⁺

EXAMPLE 87

[1663] A mixture of1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2,3-dimethoxybenzyl)piperazine(0.192 g), 3,3-dimethyl-4-(4-chloro-2-butynyl)morpholinine hydrochloride(0.106 g), potassium carbonate (0.167 g) and potassium iodide (67 mg) inN,N-dimethylformamide (1.3 ml) was stirred at 65° C. for 90 minutes andcooled. The mixture was poured into ice-water (30 ml) and the whole wasadjusted to pH 9 with sodium bicarbonate, and extracted with ethylacetate (30 ml). The extract was washed with brine (30 ml), dried oversodium sulfate and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel (8 g) using a mixedsolvent of dichloromethane and methanol (40:1). The fractions containingthe objective compound were collected and evaporated under reducedpressure to give a colorless oil of1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2,3-dimethoxybenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine.The oil was dissolved in ethyl acetate (2 ml) and the solution wastreated with 4N hydrogen chloride in ethyl acetate solution (0.30 ml)under ice-cooling, and evaporated under reduced pressure to givecolorless powder of1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2,3-dimethoxybenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazinedihydrochloride (0.18 g).

[1664] mp: 170° C.

[1665] IR (KBr): 2933, 2575, 1647, 1637, 1433, 1281, 1186, 1136 cm⁻¹

[1666] NMR (DMSO-d₆, δ): 1.33 (3H, s), 1.41 (3H, s), 2.60-5.20 (19H, m),3.75 (6H, s), 6.50-7.00 (3H, m), 7.50-8.20 (3H, m)

[1667] MASS (APCI): 642 (M+H)⁺ (free)

EXAMPLE 88

[1668] The following compound was obtained according to a similar mannerto that of Example 86.

[1669]1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(benzyloxycarbonyl)-2-[(1H-indol-2-yl)methyl]piperazine

[1670] IR (KBr): 1714, 1699, 1684, 1647, 1635, 1458, 1281 cm⁻¹

[1671] NMR (DMSO-d₆, δ): 2.60-5.10 (9H, m), 5.15 (2H, s), 5.98-8.48(13H, m), 10.58-11.04 (1H, m)

[1672] MASS (APCI):590 (M+H)⁺

EXAMPLE 89

[1673] The following compounds were obtained according to a similarmanner to that of Example 87.

[1674] (1)1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-2-yl)-methyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazinedihydrochloride

[1675] mp: 185° C.

[1676] IR (KBr): 1651, 1647, 1637, 1281, 1188, 1136 cm⁻¹

[1677] NMR (DMSO-d₆, δ): 1.31 (3H, s), 1.40 (3H, s), 3.00-5.22 (19H, m),6.02-6.40 (1H, m), 6.90-8.20 (7H, m), 11.70-11.17 (1H, m)

[1678] MASS (APCI): 621 (M+H)⁺ (free)

[1679] (2)1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-methoxybenzyl)-4-[-(3,3-dimethyl)morpholino-2-butynyl]piperazinedihydrochloride

[1680] mp: 223-225° C.

[1681] IR (KBr): 3600-3300, 2900, 2600-2300, 1647, 1635, 1458, 1435,1280 cm⁻¹

[1682] NMR (DMSO-d₆, δ): 1.32 (3H, s), 1.40 (3H, s), 2.8-5.2 (22H, m),6.5-8.20 (7H, m), 12.1-12.6 (2H, m)

[1683] MASS (APCI): 612 (M+H)⁺ (free)

EXAMPLE 90

[1684] The following compounds were obtained according to a similarmanner to that of Example 9.

[1685] (1)(2R)-4-[4-(3,3-Dimethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]-1-[3-(methylamino)-5-(trifluoromethyl)benzoyl]piperazinedihydrochloride

[1686] mp: 215-230° C.

[1687] [α]_(D) ²⁷: +41.8° (C=0.5, MeOH)

[1688] IR (KBr): 3600-3300, 2900, 2600-2300, 1645, 1624, 1614, 1458,1419 cm⁻¹

[1689] NMR (DMSO-d₆, δ):1.20-1.50 (6H, m), 2.69 (3H, s), 2.90-5.30 (19H,m), 6.55-7.90 (9H, m), 10.98 (1H, br s), 11.90-12.60 (2H, m)

[1690] MASS (APCI):582 (M+H)⁺ (free)

[1691] (2)(2R)-1-[3-(Dimethylamino)-5-(trifluoromethyl)benzoyl]-4-[4-(3,3-dlmethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]piperazinedihydrochloride

[1692] mp: 210-225° C.

[1693] [α]_(D) ²⁷: +31.8° (C=0.5, MeOH)

[1694] IR (KBr): 3600-3300, 2900, 2600-2300, 1653, 1647, 1635, 1558,1541, 1508, 1473, 1458, 1419 cm⁻¹

[1695] NMR (DMSO-d₆, δ): 1.20-1.50 (6H, m), 2.70-5.28 (19H, m), 2.94(6H, s), 6.48-7.90 (8H, m), 10.99 (1H, br s), 12.00-12.50 (2H, m)

[1696] MASS (APCI): 590 (M+H)⁺ (free)

[1697] (3)(2R)-4-[4-(3,3-Dimethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]-1-[3-nitro-5-(trifluoromethyl)-benzoyl]piperazinedihydrochloride

[1698] mp: 198-220° C.

[1699] IR (KBr): 3600-3300, 2900, 2600-2300, 1645, 1635, 1543, 1471,1458, 1421, 1358, 1331 cm⁻¹

[1700] NMR (DMSO-d₆, δ): 1.33 (3H, s), 1.41 (3H, s), 2.80-5.22 (19H, m),6.50-8.62 (8H, m), 10.99 (1H, s), 11.80-12.60 (2H, m)

[1701] MASS (APCI): 598 (M+H)⁺ (free)

[1702] (4)(2R)-2-(3,4-Dimethylbenzyl)-4-[4-(3,3-dimethyl-morpholino)-2-butynyl]-1-[3-(methylamino)-5-(trifluoromethyl)benzoyl]piperazinedihydrochloride

[1703] mp: 195-205° C.

[1704] [α]_(D) ²⁷: +10.8° (C=0.5, MeOH)

[1705] IR (KBr): 3600-3300, 2900, 2600-2300, 1647, 1635, 1616, 1456,1419 cm⁻¹

[1706] NMR (DMSO-d₆, δ): 1.32 (3H, s), 1.40 (3H, s), 2.00-2.30 (6H, m),2.70 (3H, s), 2.90-5.20 (19H, m), 6.20-7.20 (7H, m), 12.22 (2H, br s)

[1707] MASS (APCI): 571 (M+H)⁺ (free)

[1708] (5)(2R)-1-[3-(Dimethylamino)-5-(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazinedihydrochloride

[1709] mp: 108-185° C.

[1710] [α]_(D) ²⁷: +8.80° (C=0.5, MeOH)

[1711] IR (KBr): 3600-3300, 2900, 2600-2300, 1647, 1635, 1616, 1608,1506, 1456, 1425 cm⁻¹

[1712] NMR (DMSO-d₆, δ): 1.32 (3H, s), 1.40 (3H, s), 2.02-2.30 (6H, m),2.95 (6H, s), 3.00-5.25 (19H, m), 6.20-7.20 (6H, m), 12.28 (2H, br s)

[1713] MASS (APCI): 585 (M+H)⁺ (free)

[1714] (6)(2R)-2-(3,4-Dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl3-1-[3-nitro-5-(trifluoromethyl)-benzoyl]piperazinedihydrochloride

[1715] mp: 157-200° C.

[1716] [α]_(D) ²⁶: +19.50 (C=0.5, MeOH)

[1717] IR (KBr): 3600-3300, 2900, 2600-2300, 1647, 1637, 1543, 1456,1423, 1356, 1330, 1319 cm⁻¹

[1718] NMR (DMSO-d₆, δ): 1.33 (3H, s), 1.41 (3H, s), 1.95-2.34 (6H, m),2.62-5.20 (19H, m), 6.60-8.60 (6H, m), 12.10-12.50 (2H, m)

[1719] MASS (APCI): 587 (M+H)⁺ (free)

PREPARATION 72

[1720] The following compounds were obtained by a similar manner to thatof Preparation 38.

[1721] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-(2-hydroxyethyl)piperazine

[1722] IR (Neat): 3300, 2930, 2800, 1623 cm⁻¹

[1723] NMR (DMSO-d₆,δ): 2.00-5.00 (14H, m), 6.60-8.28 (8H, m), 10.86(1H, s)

[1724] MASS (APCI): 500 (M+H)⁺

[1725] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-hydroxyethyl)piperazine

[1726] IR (Neat): 3400, 1640, 1430, 1280, 1170 cm⁻¹

[1727] NMR (DMSO-d₆, δ): 2.00-5.00 (20H, m), 6.60-8.20 (6H, m)

PREPARATION 73

[1728] The following compounds were obtained by a similar manner to thatof Example 39.

[1729] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-(2-methanesulfonyloxyethyl)piperazine

[1730] IR (Neat): 3340, 3300, 3000, 2930, 2800, 1624 cm⁻¹

[1731] NMR (DMSO-d₆, δ): 2.10-4.70 (13H, m), 3.24 (3H, s), 6.26-8.28(8H, m), 10.90 (1H, s)

[1732] MASS (APCI): 578 (M+H)⁺

[1733] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-methanesulfonyloxyethyl)piperazine

[1734] IR (Neat): 1640, 1430, 1280, 1150 cm⁻¹

[1735] NMR (DMSO-d₆, δ): 2.00-5.00 (23H, m), 6.60-8.20 (6H, m)

[1736] MASS (APCI): 567, 489

PREPARATION 74

[1737] The following compound was obtained by a similar manner to thatof Preparation 37.

[1738](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-(4-chloro-2-butynyl)piperazine

[1739] IR (Neat): 3300, 3050, 2800, 2600, 1630, 1430 cm⁻¹

[1740] NMR (CDCl₃, δ): 2.20-5.30 (13H, m), 6.75-8.20 (8H, m)

[1741] MASS (APCI): 542 (M+H)⁺

PREPARATION 75

[1742] (1) The following compound was obtained by a similar manner tothat of Preparation 46-(4).

[1743]1-Acetyl-3-(3-methoxy-4-methylphenyl)methylene-2,5-piperazinedione

[1744] NMR (DMSO-d₆, δ): 2.17 (3H, s), 2.50 (3H, s), 3.83 (3H, s), 4.37(2H, s), 6.95 (1H, s), 7.08-7.22 (3H, m), 10.33 (1H, s)

[1745] MASS (APCI): 289 (M+H)⁺

[1746] (2) The following compound was obtained by a similar manner tothat of Preparation 46-(5).

[1747] 3-(3-Methoxy-4-methylbenzyl)-2,5-piperazinedione

[1748] NMR (DMSO-d₆, δ): 2.11 (3H, s), 2.75 (1H, d, J=17.4Hz), 2.84 (1H,m), 3.05 (1H, dd, J=13.4, 4.5Hz), 3.35 (1H, m), 3.73 (3H, s), 4.04 (1H,m), 6.63 (1H, d, J=7.4Hz), 6.73 (1H, s), 7.03 (1H, d, J=7.4Hz), 7.88(1H, m), 8.13 (1H, m)

[1749] MASS (APCI): 249 (M+H)⁺

[1750] (3) The following compound was obtained by a similar manner tothat of Preparation 47-(3).

[1751] 2-(3-Methoxy-4-methylbenzyl)piperazine dihydrobromide

[1752] NMR (DMSO-d₆, δ): 2.13 (3H, s), 2.78-3.78 (9H, m), 3.81 (3H, s),6.73-7.15 (3H, m), 9.11 (4H, m)

[1753] MASS (APCI): 221 (M+H)⁺ (free)

[1754] (4) A stirred solution of 2-(3-methoxy-4-methylbenzyl)-piperazinedihydrobromide (240 mg) in 48% hydrobromic acid (8 ml) was heated underreflux for 48,hours. After cooling, the mixture was concentrated underreduced pressure. The residue was triturated with ethyl acetate and theresulting precipitates were collected by filtration, and washed withethyl acetate to give 2-(3-hydroxy-4-methylbenzyl)piperazinedihydrobromide (175 mg) as a powder.

[1755] NMR (DMSO-d₆, δ): 2.11 (3H, s), 2.67-3.78 (9H, m), 6.70-6.95 (3H,m), 9.09 (4H, m)

[1756] MASS (APCI): 207 (M+H)⁺ (free)

EXAMPLE 91

[1757] The following compounds were obtained by a similar manner to thatof Example 84.

[1758] (1)1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-(3-hydroxy-4-methylbenzyl)-piperazinedihydrochloride

[1759] NMR (DMSO-d₆, δ): 1.32-1.38 (6H, m), 2.08 (3H, s), 2.68-5.03(20H, m), 6.18-8.20 (6H, m)

[1760] MASS (APCI): 612 (M+H)⁺ (free)

[1761] (2)1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-(3-methoxy-4-methylbenzyl)piperazinedihydrochloride

[1762] NMR (DMSO-d₆, δ): 1.33-1.38 (6H, m), 2.10 (3H, s), 2.73-5.10(22H, m), 6.40-8.18 (6H, m)

[1763] MASS (APCI): 626 (M+H)⁺ (free)

[1764] (3)1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-(4-hydroxy-3-methylbenzyl)piperazinedihydrochloride

[1765] NMR (DMSO-d₆, δ): 1.32-1.38 (6H, m), 2.09 (3H, s), 2.73-4.98(20H, m), 6.55-8.20 (6H, m)

[1766] MASS (APCI): 612 (M+H)⁺ (free)

PREPARATION 76

[1767] The following compound was obtained according to a similar mannerto that of Preparation 75-(4).

[1768] 2-(4-Hydroxy-3-methylbenzyl)piperazine dihydrobromide

[1769] NMR (DMSO-d₆, δ): 2.10 (3H, s), 2.67-3.57 (9H, m), 6.57-7.11 (3H,m), 9.12-9.39 (5H, m)

[1770] MASS (APCI): 207 (M+H)⁺ (free)

PREPARATION 77

[1771] (1) The following compound was obtained according to a similarmanner to that of Preparation 46-(4).

[1772] 1-Acetyl-3-(3-nitrophenyl)methylene-2,5-piperazinedione

[1773] mp: 190-200° C.

[1774] NMR (DMSO-d₆, δ): 2.51 (3H, s), 4.32 (2H, s), 7.03 (1H, s), 7.65(1H, m), 7.94 (1H, d, J=7.8Hz), 8.16 (1H, dd, J=1.6, 7.8Hz), 8.37 (1H,d, J=1.6Hz), 10.80 (1H, br s)

[1775] MASS (APCI): 290 (M+H)⁺79

[1776] (2) A mixture of1-acetyl-3-(3-nitrophenyl)methylene-2,5-piperazinedione (10.2 g),triethylamine (6.43 ml) and di-tert-butyl dicarbonate (23.5 g) inN,N-dimethylformamide (50 ml) was hydrogenated over 10% palladium-carbon(50% wet, 1 g) at room temperature under 2-3 atmospheres. After removalof catalyst by filtration, the filtrate was concentrated by evaporation,the residue was partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried over magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel using a mixture of dichloromethane andmethanol (20:1). The fractions containing the objective compound werecollected and evaporated under reduced pressure. The resultingprecipitates were collected by filtration and washed with methanol togive 1-acetyl-3-[3-(tert-butoxycarbonylamino)benzyl]-2,5-piperazinedione(1.3 g) as colorless powders.

[1777] mp: 189-190° C.

[1778] IR (KBr): 3334, 1727, 1704, 1681, 1602, 1590, 1540 cm⁻¹

[1779] NMR (DMSO-d₆, δ): 1.46 (9H, s), 2.43 (3H, s), 2.94 (1H, dd,J=6.4, 14.2Hz), 3.10 (1H, dd, J=6.4, 14.2), 3.15 (1H, d, J=17.4Hz), 3.96(1H, d, J=17.4Hz), 4.30-4.35 (1H, m), 6.58 (1H, d, J=7.lHz), 7.15 (1H,m), 7.23 (1H, d, J=7.Hz), 7.43 (1H, s), 7.42 (1H, d, J=2.8Hz), 9.32 (1H,s)

[1780] MASS (APCI): 306 (M−(CH₃)₃)⁺

[1781] (3) The following compound was obtained according to a similarmanner to that of Preparation 46-(5).

[1782] 3-[3- (tert-Butoxycarbonylamino)benzyl]-2,5-piperazinedione

[1783] mp: 230-233° C.

[1784] IR (KBr): 3301, 3212, 3083, 2981, 1716, 1675, 1608 cm⁻¹

[1785] NMR (DMSO-d₆, δ): 1.47 (9H, s), 2.89 (1H, dd, J=5.3, 9.1Hz), 2.95(1H, d, J=17.0Hz), 2.96 (1H, dd, J=5.3, 9.1Hz), 3.36 (1H, dd, J=3.8,17.0Hz), 3.95-4.00 (1H, m), 6.78 (1H, d, J=7.8Hz), 7.14 (1H, m),7.30-7.35 (2H, m), 7.91 (1H, br s), 8.13 (1H, br s), 9.30 (1H, s)

[1786] MASS (APCI): 320 (M+H)⁺, 264

[1787] (4) A solution of3-[3-(tert-butoxycarbonylamino)benzyl]-2,5-piperazinedione (0.75 g) intrifluoroacetic acid (10 ml) was stirred for 4 hours at roomtemperature. After removal of the solvent by evaporation, the residuewas dissolved in a mixture of dichloromethane (10 ml) and methanol (3ml) and thereto benzaldehyde (0.742 g) and sodium triacetoxyborohydride(2.11 g) were added. The whole was stirred for 2 hours at roomtemperature and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel using a mixture ofdichloromethane and methanol (25:1). The fractions containing theobjective compound were collected and triturated with isopropyl alcoholto give 2-[3-(benzylamino)benzyl]-3,6-piperazinedione (0.43 g) ascolorless crystals.

[1788] mp: 160-161° C.

[1789] IR (KBr): 3168, 3056, 2975, 2867, 1677, 1606, 1550 cm⁻¹

[1790] NMR (DMSO-d₆, δ): 2.86 (1H, d, J=17.2Hz), 2.82 (1H, dd, J=4.8,13.3Hz), 2.92 (1H, dd, J=4.8, 13.3Hz), 3.33 (1H, dd, J=3.0, 17.2Hz),3.96 (1H, d, J=3.0Hz), 4.21 (2H, d, J=6.0Hz), 6.16 (1H, m), 6.33 (1H, d,J=7.4Hz), 6.41-6.45 (2H, m), 6.92 (1H, m), 7.18-7.33 (5H, m), 7.78 (1H,br s), 8.04 (1H, d, J=2.2Hz)

[1791] MASS (APCI): 310 (M+H)⁺

[1792] (5) A suspension of 2-[3-(benzylamino)benzyl]-3,6-piperazinedione(0.45 g), 37% aqueous formaldehyde (81 mg), sodium triacetoxyborohydride(0.62 g) and acetic acid (175 mg) in a mixture of 1,2-dichloroethane (15ml) and N,N-dimethylformamide (5 ml) was stirred for 5 hours at roomtemperature. Then additional 37% aqueous formaldehyde (0.1 ml), aceticacid (0.2 ml) and sodium triacetoxyborohydride (0.60 g) were added tothe reaction mixture and the whole was stirred for further 2 hours. Themixture was concentrated under reduced pressure and the residue waspurified by column chromatography on silica gel using a mixture ofdichloromethane and methanol (10:1). The fractions containing theobjective compound were collected and evaporated under reduced pressure.The resulting precipitates were collected by filtration and washed withisopropyl alcohol to give2-[3-(N-benzyl-N-methylamino)benzyl]-3,6-piperazinedione (0.46 g) ascolorless crystals.

[1793] NMR (DMSO-d₆, δ): 2.71-3.03 (3H, m), 2.94 (3H, s), 3.27-3.37 (1H,m), 4.00-4.05 (1H, m), 4.53 (2H, s), 6.42 (1H, d, J=7.5Hz), 6.57-6.61(2H, m), 6.98-7.06 (1H, m), 7.16-7.34 (5H, m), 7.85 (1H, s), 8.09 (1H,d, J=2.2Hz)

[1794] MASS (APCI): 324 (M+H)⁺

[1795] (6) The following compound was obtained according to a similarmanner to that of Preparation 49-(4).

[1796] 2-[3-(N-Benzyl-N-methylamino)benzyl]piperazine

[1797] The compound was used to the next step without furtherpurification.

PREPARATION 78

[1798] The following compound was obtained according to a similar mannerto that of Preparation 50.

[1799] 1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-(N-methylamino)-benzyl]piperazine

[1800] NMR (CDCl₃, δ): 2.20-5.20 (10H, m), 2.99 (3H, s), 6.00-7.40 (7H,m), 8.16 (1H, s)

[1801] MASS (APCI): 446 (M+H)⁺

EXAMPLE 92

[1802] The following compound was obtained according to a similar mannerto that of Preparation 49-(5) through a similar manner to that ofExample 86.

[1803] 1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[3-N-benzyl-N-methylamino)benzyl]-4-(benzyloxycarbonyl)piperazine

[1804] IR (Neat): 1705, 1645, 1605, 1505 cm⁻¹

[1805] NMR (CDCl₃, δ): 2.60-4.80 (14H, m), 5.18 (2H, s), 6.10-7.40 (16H,m), 7.84 (1H, s)

[1806] MASS (APCI): 670 (M+H)⁺

EXAMPLE 93

[1807] The following compound was obtained according to a similar mannerto that of Example 87.

[1808] 1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-[3-(N-methylamino)benzyl]piperazine

[1809] IR (Neat): 3400, 1680, 1640, 1610 cm⁻¹

[1810] NMR (CDCl₃, δ): 1.06 (6H, br s), 2.10-5.20 (20H, m), 3.34 (3H,s), 5.95-7.80 (7H, m)

[1811] MASS (APCI): 611 (M+H)⁺

[1812] its trihydrochloride

[1813] mp: 192-195° C.

[1814] IR (KBr): 3500-3300, 3000-2800, 2700-2300, 1644 cm⁻¹

[1815] NMR (CDCl₃, δ): 1.36 (6H, s), 2.71-2.81 (3H, m), 3.20-5.20 (20H,m), 6.60-8.21 (7H, m)

[1816] MASS (APCI): 611 (M+H)⁺ (free)

EXAMPLE 94

[1817] A suspension of1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-[3-(N-methylamino)-benzyl]piperazine(0.19 g), 37% aqueous formaldehyde (50 μl), sodium triacetoxyborohydride(79 mg) and acetic acid (22 μl) in dichloromethane (5 ml) was stirredfor 2 hours at room temperature. Then additional 37% aqueousformaldehyde (25 μl), acetic acid (10 μl) and sodiumtriacetoxyborohydride (40 mg) were added to the reaction mixture and thewhole was stirred for further 1 hour. The mixture was poured intoaqueous saturated sodium hydrogen carbonate solution and extracted withdichlorolmethane. The extract was dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using a mixture of dichloromethane andmethanol (40:1). The fractions containing the objective compound werecollected and evaporated under reduced pressure and treated with 4Nhydrogen chloride in ethyl acetate solution to give1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-(N,N-dimethylamino)benzyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazinetrihydrochloride (0.21 g).

[1818] mp: 205-210° C.

[1819] IR (KBr): 3500-3300, 2900-2500, 1644 cm⁻¹

[1820] NMR (DMSO-d₆, δ): 1.32 (3H, s), 1.41 (3H, s), 2.91 (3H, 3), 3.03(3H, s), 3.20-5.20 (19H, m), 6.40-8.25 (7H, m)

[1821] MASS (APCI): 625 (M+H)⁺ (free)

1. A compound of the formula

wherein Y is bond or lower alkylene, R¹ is aryl which may havesubstituent(s), R² is aryl or indolyl, each of which may havesubstituent(s), R³ is hydrogen or lower alkyl, R⁴ ispyridyl(lower)alkylamino(lower)alkynyl; N-(loweralkyl)-N-[pyridyl(lower)alkyl]amino-(lower)alkyl;hydroxy(lower)alkoxy(lower)alkyl; loweralkanoyl(lower)alkoxy(lower)alkyl; phenyl(lower)alkyl which hashydroxy(lower)alkyl or morpholinyl(lower)alkyl; ar(lower)alkoxycarbonyl;(2-pyridyl)(lower)alkyl which may have 1 to 3 substituent(s) selectedfrom the group consisting of lower alkyl, lower alkoxy, loweralkoxycarbonyl, mono(or di or tri)halo(lqwer)alkyl and halogen;(3-pyridyl)propyl which may have lower alkoxy or amino; (3-pyridyl)butylwhich may have lower alkoxy or amino; pyridyl(lower)alkenyl which mayhave lower alkoxy or amino; (2-pyridyl)(lower)alkynyl which may have 1to 3 substituent(s) selected from the group consisting of lower alkyl,lower alkoxy, lower alkoxycarbonyl, mono(or di or tri)halo(lower)alkyland halogen; (3-pyridyl)(lower)alkynyl which may have lower alkoxy oramino; pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which mayhave substituent(s); imidazolyl(lower)alkyl which may have 1 or 2substituent(s) selected from the group consisting of lower alkyl, loweralkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di ortri)halo(lower)alkyl and halogen; pyrazolyl(lower)alkyl which may havehydroxy(lower)alkyl, carboxy(lower)alkyl, loweralkoxycarbonyl(lower)alkyl, morpholinyl(lower)alkyl ormorpholinylcarbonyl(lower)alkyl; thiazolyl(lower)alkyl which may havelower alkyl; piperidyl(lower)alkyl which may have hydroxy(lower)alkyl orlower alkoxy; morpholinyl(lower)alkyl which has 1 or 2 substituent(s)selected from the group consisting of ethyl, hydroxy(lower)alkyl,halo(lower)alkyl and lower alkoxy(lower)alkyl; morpholinyl(lower)alkylwhich has lower alkyl and lower alkoxy(lower)alkyl;(3,5-dimethylmorpholino)(lower)alkyl; morpholino(lower)alkenyl which mayhave lower alkyl or lower alkoxy(lower)alkyl; (2- or3-morpholinyl)(lower)alkenyl which may have lower alkoxycarbonyl;pyrrolidinyl(lower)alkynyl which may have lower alkoxy(lower)alkyl;morpholinyl(lower)alkynyl which may have 1 or 2 substituent(s) selectedfrom the group consisting of ethyl, propyl, isopropyl, isobutyl,spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl,carboxy(lower)alkyl, di(lower alkyl)carbamoyl, lower alkoxycarbonyl andhalo(lower)alkyl; morpholinyl(lower)alkynyl which has methyl and loweralkoxy; (dimethylmorpholino)(lower)alkynyl;homomorpholinyl(lower)alkynyl which have halogen;(morpholinylamino)propyl which may have lower alkanoyl;thiomorpholinyl(lower)alkynyl which may have substituent(s);homomorpholinylamino(lower)alkyl; thiomorpholinylamino(lower)alkyl; orsaturated heterocyclicimino(lower)alkyl, saturatedheterocyclicaminocarbonyl(lower)alkyl or saturatedheterocyclic(lower)alkoxy(lower)alkyl, each of which may havesubstituent(s), provided that when R⁴ is2-[N-methyl-N-(3-pyridylmethyl)amino]ethyl, 3-(3-pyridyl)propyl,3-(3-pyridyl)-2-propynyl, 4-[(2-methoxymethyl)pyrrolidino]-2-butynyl,4-thiomorpholino-2-butynyl, 3-(morphlinoamino)propyl,4-morpholino-2-butenyl, 4-morpholino-2-butynyl, or4-(3,3-dimethylmorpholino)-2-butynyl, then R¹ is not3,5-bis(trifluoromethyl)phenyl, and a salt thereof.
 2. The compound ofclaim 1, in which Y is lower alkylene, R¹ is C₆-C₁₀ aryl which may have1 or 2 substituent(s) selected from the group consisting of mono(or dior tri)halo(lower)alkyl, halogen, lower alkylamino, di(lower)alkylaminoand nitro, R² is C₆-C₁₀ aryl or indolyl, each of which may have 1 to 3substituent(s) selected from the group consisting of lower alkyl,mono(or di or tri)halo(lower)alkyl, lower alkylenedioxy, hydroxy,hydroxy(lower)alkyl, lower alkoxy, lower alkylamino anddi(lower)alkylamino, R³ is hydrogen, and R⁴ ispyridyl(lower)alkylamino(lower)alkynyl; (2-pyridyl)propyl which may have1 to 3 substituent(s) selected from the group consisting of lower alkyl,lower alkoxy, lower alkoxycarbonyl, mono(or di or tri)halo(lower)alkyland halogen; pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of whichmay have 1 or 2 substituent(s) selected from the group consisting oflower alkyl, ar(lower)alkyl and pyridyl(lower)alkyl;imidazolyl(lower)alkyl which has 1 or 2 substituent(s) selected from thegroup consisting of lower alkyl, lower alkynyl, ar(lower)alkyl,pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyl and halogen;(2-methyl-1H-imidazol-4-yl)(lower)alkyl which has 1 or 2 substituent(s)selected from the group consisting of isopropyl, lower alkynyl,ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di or tri)halo(lower)alkyland halogen; (5-methyl-1H-imidazol-4-yl)(lower)alkyl which has 1 or 2substituent(s) selected from the group consisting of isopropyl, loweralkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, mono(or di ortri)halo(lower)alkyl and halogen; piperidyl(lower)alkyl which may havehydroxy(lower)alkyl or lower alkoxy; morpholinyl(lower)alkyl which has 1or 2 substituent(s) selected from the group consisting of ethyl,hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy(lower)alkyl;morpholinyl(lower)alkyl which has lower alkyl and loweralkoxy(lower)alkyl; (3,5-dimethylmorpholino)(lower)alkyl;morpholino(lower)alkenyl which may have lower alkyl or loweralkoxy(lower)alkyl; (2- or 3-morpholinyl)(lower)alkenyl which may havelower alkoxycarbonyl; pyrrolidinyl(lower)alkynyl which may have loweralkoxy(lower)alkyl; morpholinyl(lower)alkynyl which may have 1 or 2substituent(s) selected from the group consisting of ethyl, propyl,isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl,hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl,lower alkoxycarbonyl and halo(lower)alkyl; morpholinyl(lower)alkynylwhich has methyl and lower alkoxy(lower)alkyl;(dimethylmorpholino)(lower)alkynyl; or homomorpholinyl(lower)alkynylwhich may have halogen.
 3. The compound of claim 2, in which Y is loweralkylene, R¹ is phenyl which has 1 or 2 substituent(s) selected from thegroup consisting of trihalo(lower)alkyl, halogen, lower alkylamino,di(lower)alkylamino and nitro, R² is phenyl or indolyl, each of whichhave 1 or 2 substituent(s) selected from the group consisting of loweralkyl, trihalo(lower)alkyl, lower alkylenedioxy, hydroxy,hydroxy(lower)alkyl, lower alkoxy, lower alkylamino anddi(lower)alkylamino, R³ is hydrogen, and R⁴ is (2-pyridyl)propyl whichmay have 1 to 3 substituent(s) selected from the group consisting oflower alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl andhalogen; morpholinyl(lower)alkyl which has 1 or 2 substituent(s)selected from the group consisting of ethyl, hydroxy(lower)alkyl,halo(lower)alkyl and lower alkoxy(lower)alkyl; morpholinyl(lower)alkynylwhich may have 1 or 2 substituent(s) selected from the group consistingof ethyl, propyl, isopropyl, isobutyl, spirocyclo(lower)alkyl, loweralkoxy(lower)alkyl, hydroxy(lower)alkyl, carboxy(lower)alkyl, di(loweralkyl)carbamoyl, lower alkoxycarbonyl and halo(lower)alkyl.
 4. Acompound of claim 3, which is selected from the group consisting of (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(4-((3S)-3-ethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]piperazine,(2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((2S)-2-methoxymethyl-morpholino)ethyl]piperazine,(3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-((3R)-3-methoxymethyl-morpholino)ethyl]piperazine,(4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl[-2-(3,4-dimethylbenzyl)-4-[2-((2R)-2-methoxymethyl-morpholino)ethyl]piperazine,(5)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[2-((2S)-2-methoxymethyl-morpholino)ethyl]piperazine,and (6)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-((3R)-3-ethylmorpholino)ethyl]-2-[(1H-indol-3-yl)-methyl]piperazineor a pharmaceutically acceptable salt thereof.
 5. A process for thepreparation of the compound of claim 1 or a salt thereof, whichcomprises, (1) reacting a compound of the formula (II):

wherein R¹, R² ₁ R³ and Y are each as defined in claim 1, or a saltthereof, with a compound of the formula (III): W₁-R⁴  (IV) wherein R⁴ isas defined in claim 1 and W₁ is a leaving group, or a salt thereof togive a compound of the formula (I):

wherein R¹ ₁ R², R³, R⁴ and Y are each as defined in claim 1, or a saltthereof, (2) subjecting a compound of the formula (Ia):

wherein R¹, R², R³ and Y are each as defined above, R⁵ is 2-pyridylwhich may have 1 to 3 substituent(s) selected from the group consistingof lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono(or di ortri)halo(loweralkyl and halogen; or 3-pyridyl which may have loweralkoxy or amino, and Z₁ is lower alkynylene, or a salt thereof to areduction reaction to give a compound of the formula (Ib):

wherein R¹, R², R³, Y and R⁵ are each as defined above, and X₁ is loweralkylene, or a salt thereof, (3) reacting a compound of the formula(III):

wherein R¹ ₁ R², R³ and Y are each as defined above, and X₂ is loweralkylene, or its reactive derivative at the carboxy group or a saltthereof with a compound of the formula (V): H₂N—R⁶  (V) wherein R⁶issaturated heterocyclic which may have substituent(s), or a salt thereofto give a compound (Ic):

wherein R¹, R², R³, R⁶, X₂ and Y are each as defined above, (4) reactinga compound of the formula (VI):

wherein R¹, R², R³ and Y are each as defined above, X₃ is lower alkyleneand W₂ is a leaving group, or a salt thereof with a compound of theformula (VII): H—R⁷  (VII) wherein R⁷ is pyridyl(lower)alkylamino;N-(lower alkyl)-N-(pyridyl(lower)alkyl]-amino; 1-imidazolyl which mayhave 1 or 2 substituent(s) selected from the group consisting of loweralkyl, lower alkynyl, ar(lower)alkyl, pyridyl(lower)alkyl, rmono(or dior tri)halo(lower)alkyl and halogen; 1-pyrazolyl which may havehydroxy(lower)alkyl, carboxy(lower)alkyl, loweralkoxycarbonyl(lower)alkyl, morpholinyl(lower)alkyl ormorpholinylcarbonyl(lower)alkyl; piperidino which may havehydroxy(lower)alkyl or lower alkoxy; morpholino which has 1 or 2substituent(s) selected from the group consisting of ethyl,hydroxy(lower)alkyl, halo(lower)alkyl and lower alkoxy-(lower)alkyl;morpholino which has lower alkyl and lower alkoxy(lower)alkyl;3,5-dimethylmorpholino; morpholinylamino which may have lower alkanoyl;homomorpholinylamino; or thiomorpholinylamino, or a salt thereof to givea compound of the formula (Id):

wherein R¹, R², R³, R⁷, X₃ and Y are each as defined above, or a saltthereof, (5) reacting a compound of the formula (VIII):

wherein R¹ ₁, R², R³ and Y are each as defined above, Z₂ is loweralkenylene, and W₃ is a leaving group, or a salt thereof with a compoundof the formula (IX): H—R⁸  (IX) wherein R⁸ is morpholino which may havelower alkyl or lower alkoxy(lower)alkyl, or a salt thereof to give acompound of the formula (Ie):

wherein R¹, R², R³, R⁸, Y and Z₂ are as defined as above, or a saltthereof, (6) reacting compound of the formula (X):

wherein R¹, R², R³ and Y are each as defined above, Z₃ is a loweralkynylene and W₄ is a leaving group, or a salt thereof with a compoundof the formula (XI): H—R⁹  (XI) wherein R⁹ is pyrrolidino which may havelower alkoxy(lower)alkyl; morpholino which may have 1 or 2substituent(s) selected from the group consisting of ethyl, propyl,isopropyl, isobutyl, spirocyclo(lower)alkyl, lower alkoxy(lower)alkyl,hydroxy(lower)alkyl, carboxy(lower)alkyl, di(lower alkyl)carbamoyl,lower alkoxycarbonyl and halo(lower)alkyl; morpholino which has methyland lower alkoxy; dimethylmorpholino; or homomorpholino which hashalogen, or a salt thereof to give a compound of the formula (If):

wherein R¹, R², R³, R⁹, Y and Z₃ are each as defined above, or a saltthereof.
 6. A pharmaceutical composition which comprises, as an activeingredient, a compound of claim 1 or a pharmaceutically acceptable saltthereof in admixture with pharmaceutically acceptable carriers.
 7. Acompound of claim 1 for use as a medicament.
 8. A method for treating orpreventing Tachykinin-mediated diseases which comprises administering aneffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt thereof to human being or animals.
 9. A compound ofclaim 1 for use as Tachykinin antagonist.
 10. Use of a compound of claim1 for manufacture of a medicament for treating or preventingTachykinin-mediated diseases.